Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0007409 axonogenesis	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation. Full-length APP regulates axon development. APP knockout mice show defects in axonogenesis. sAPPalpha promotes neurite outgrowth while full-length APP with Fe65/Mena inhibits branching to ensure directional growth. Reason: Core biological process. Well-supported by knockout studies and mechanistic understanding.
GO:0007417 central nervous system development	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference (IBA) from GO_REF:0000033. IBA annotations undergo extensive phylogenetic review and are generally reliable. Reason: IBA annotation supported by phylogenetic analysis.
GO:0005769 early endosome	IBA GO_REF:0000033	ACCEPT	Summary: Cellular component annotation supported by APP trafficking and localization studies. APP is found in multiple cellular compartments consistent with its complex processing pathway (UniProt P05067). Reason: Well-documented localization consistent with APP biology.
GO:0005102 signaling receptor binding	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference (IBA) from GO_REF:0000033. IBA annotations undergo extensive phylogenetic review and are generally reliable. Reason: IBA annotation supported by phylogenetic analysis.
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: Cellular component annotation supported by APP trafficking and localization studies. APP is found in multiple cellular compartments consistent with its complex processing pathway (UniProt P05067). Reason: Well-documented localization consistent with APP biology.
GO:0030546 signaling receptor activator activity	IBA GO_REF:0000033	ACCEPT	Summary: Abeta42 activates FPR2 (formyl peptide receptor 2), inducing chemotaxis and oxidant stress in phagocytes (PMID:11316806). Note: this is primarily an Abeta cleavage product function. Reason: Supported by literature, though applies to Abeta rather than full-length APP.
GO:0005794 Golgi apparatus	IBA GO_REF:0000033	ACCEPT	Summary: Cellular component annotation supported by APP trafficking and localization studies. APP is found in multiple cellular compartments consistent with its complex processing pathway (UniProt P05067). Reason: Well-documented localization consistent with APP biology.
GO:0045121 membrane raft	IBA GO_REF:0000033	ACCEPT	Summary: Cellular component annotation supported by APP trafficking and localization studies. APP is found in multiple cellular compartments consistent with its complex processing pathway (UniProt P05067). Reason: Well-documented localization consistent with APP biology.
GO:0009986 cell surface	IBA GO_REF:0000033	ACCEPT	Summary: Cellular component annotation supported by APP trafficking and localization studies. APP is found in multiple cellular compartments consistent with its complex processing pathway (UniProt P05067). Reason: Well-documented localization consistent with APP biology.
GO:0004867 serine-type endopeptidase inhibitor activity	IEA GO_REF:0000120	ACCEPT	Summary: ISOFORM-SPECIFIC: KPI-containing isoforms (APP751/770) only. The Kunitz protease inhibitor domain is absent from the neuronal APP695 isoform. Reason: IEA annotation consistent with known APP biology. Note isoform specificity.
GO:0005576 extracellular region	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation. Secreted sAPPalpha/beta and Abeta are found in extracellular region. Reason: IEA annotation consistent with known APP functions.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: AICD translocates to nucleus with Fe65 and Tip60 for transcriptional regulation. However, this remains controversial. Reason: IEA annotation consistent with known APP functions.
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation. APP cytoplasmic domain interacts with multiple adaptor proteins. Reason: IEA annotation consistent with known APP functions.
GO:0005769 early endosome	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation. APP is processed in endosomes where BACE1 cleavage occurs. Reason: IEA annotation consistent with known APP trafficking.
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation. APP is synthesized and processed through ER. Reason: IEA annotation consistent with known APP trafficking.
GO:0005794 Golgi apparatus	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation. APP transits through Golgi during maturation. Reason: IEA annotation consistent with known APP trafficking.
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation. Full-length APP is a type I transmembrane protein at plasma membrane. Reason: IEA annotation consistent with known APP functions.
GO:0005905 clathrin-coated pit	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation. APP is internalized via clathrin-mediated endocytosis. Reason: IEA annotation consistent with known APP trafficking.
GO:0006897 endocytosis	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation. APP undergoes internalization via endocytosis. Reason: IEA annotation consistent with known APP functions.
GO:0006915 apoptotic process	IEA GO_REF:0000043	ACCEPT	Summary: CLEAVAGE PRODUCT DEPENDENT: Abeta induces apoptosis (neurotoxic), while sAPPalpha is neuroprotective. Full-length APP itself has dual roles depending on processing pathway. Reason: IEA annotation consistent with APP biology but note cleavage product specificity.
GO:0007155 cell adhesion	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation. Full-length APP functions as a cell adhesion molecule via trans-dimerization. Reason: Core function of full-length APP.
GO:0007219 Notch signaling pathway	IEA GO_REF:0000043	REMOVE	Summary: APP is not a component of the Notch signaling pathway. This IEA annotation likely arises because APP and Notch are both substrates of gamma-secretase (presenilin), but sharing an enzyme does not make APP part of the Notch pathway. APP has its own distinct signaling pathway via AICD. Reason: APP is a substrate of gamma-secretase but is NOT a participant in Notch signaling. The connection is only that they share the same protease. This is an incorrect annotation that should be removed.
GO:0008201 heparin binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation. APP ectodomain binds heparin and heparan sulfate proteoglycans. Reason: IEA annotation consistent with known APP functions.
GO:0009986 cell surface	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation. Full-length APP is a type I transmembrane protein at cell surface. Reason: IEA annotation consistent with known APP localization.
GO:0010604 positive regulation of macromolecule metabolic process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: IEA annotation for positive regulation of macromolecule metabolic process. This is extremely broad and does not provide useful functional information about APP. Reason: Too broad to be informative. Over-annotation.
GO:0016020 membrane	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation. Full-length APP is a type I transmembrane protein. Reason: IEA annotation consistent with known APP localization.
GO:0030414 peptidase inhibitor activity	IEA GO_REF:0000043	ACCEPT	Summary: ISOFORM-SPECIFIC: KPI-containing isoforms (APP751/770) only. The Kunitz protease inhibitor domain is absent from neuronal APP695. Reason: IEA annotation consistent with known APP biology. Note isoform specificity.
GO:0030426 growth cone	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation. APP is localized to growth cones and regulates axon guidance. Reason: IEA annotation consistent with known APP localization and function.
GO:0031091 platelet alpha granule	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation. APP is expressed in platelets and stored in alpha granules. Reason: IEA annotation consistent with known APP expression.
GO:0031410 cytoplasmic vesicle	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation. APP is transported in vesicles along axons. Reason: IEA annotation consistent with known APP trafficking.
GO:0043005 neuron projection	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation. APP is transported to and localized in neuron projections. Reason: IEA annotation consistent with known APP localization.
GO:0043204 perikaryon	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation. APP is found in neuronal cell bodies. Reason: IEA annotation consistent with known APP localization.
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation. APP binds copper and zinc via its ectodomain and regulates metal homeostasis. Reason: Core function of APP. Well documented.
GO:0046914 transition metal ion binding	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation. APP binds copper and zinc (transition metals) via its ectodomain. Reason: Core function of APP. Well documented.
GO:0051246 regulation of protein metabolic process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: IEA annotation for regulation of protein metabolic process. This is very broad and does not provide useful functional information about APP. Reason: Too broad to be informative. Over-annotation.
GO:0140677 molecular function activator activity	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: IEA annotation for molecular function activator activity. This is extremely broad and does not specify what molecular function APP activates. Not informative. Reason: Too broad to be informative. Over-annotation.
GO:0005515 protein binding	IPI PMID:10677483 Human aspartic protease memapsin 2 cleaves the beta-secretas...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. BACE1 (memapsin 2) cleaves APP at the beta-secretase site. Functional interaction for APP processing. Reason: Generic protein binding uninformative - the specific interaction is with BACE1. Supporting Evidence: PMID:10677483 Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein.
GO:0005515 protein binding	IPI PMID:10681545 beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine r...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:10681545 beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity.
GO:0005515 protein binding	IPI PMID:11278849 beta -Amyloid peptide-induced apoptosis regulated by a novel...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:11278849 2001 Feb 20. beta -Amyloid peptide-induced apoptosis regulated by a novel protein containing a g protein activation module.
GO:0005515 protein binding	IPI PMID:11297421 Apolipoprotein A-I directly interacts with amyloid precursor...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:11297421 Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits A beta aggregation and toxicity.
GO:0005515 protein binding	IPI PMID:11724784 Jun NH2-terminal kinase (JNK) interacting protein 1 (JIP1) b...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:11724784 Nov 27. Jun NH2-terminal kinase (JNK) interacting protein 1 (JIP1) binds the cytoplasmic domain of the Alzheimer's beta-amyloid precursor protein (APP).
GO:0005515 protein binding	IPI PMID:11877420 Tyrosine phosphorylation of the beta-amyloid precursor prote...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:11877420 2002 Mar 4. Tyrosine phosphorylation of the beta-amyloid precursor protein cytoplasmic tail promotes interaction with Shc.
GO:0005515 protein binding	IPI PMID:12485888 Signal transduction through tyrosine-phosphorylated carboxy-...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:12485888 Signal transduction through tyrosine-phosphorylated carboxy-terminal fragments of APP via an enhanced interaction with Shc/Grb2 adaptor proteins in reactive astrocytes of Alzheimer's disease brain.
GO:0005515 protein binding	IPI PMID:12901838 Presenilin-1 interacts directly with the beta-site amyloid p...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:12901838 Presenilin-1 interacts directly with the beta-site amyloid protein precursor cleaving enzyme (BACE1).
GO:0005515 protein binding	IPI PMID:15896298 In cerebrospinal fluid ER chaperones ERp57 and calreticulin ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:15896298 In cerebrospinal fluid ER chaperones ERp57 and calreticulin bind beta-amyloid.
GO:0005515 protein binding	IPI PMID:16027166 BRI2 interacts with amyloid precursor protein (APP) and regu...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:16027166 2005 Jul 18. BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid beta (Abeta) production.
GO:0005515 protein binding	IPI PMID:16049941 A pilot proteomic study of amyloid precursor interactors in ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:16049941 A pilot proteomic study of amyloid precursor interactors in Alzheimer's disease.
GO:0005515 protein binding	IPI PMID:16174740 Neuronal sorting protein-related receptor sorLA/LR11 regulat...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:16174740 Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein.
GO:0005515 protein binding	IPI PMID:16286452 Gerstmann-Sträussler-Scheinker disease amyloid protein polym...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:16286452 Nov 10. Gerstmann-Sträussler-Scheinker disease amyloid protein polymerizes according to the "dock-and-lock" model.
GO:0005515 protein binding	IPI PMID:16374483 Neurofibromatosis type 1 protein and amyloid precursor prote...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:16374483 Neurofibromatosis type 1 protein and amyloid precursor protein interact in normal human melanocytes and colocalize with melanosomes.
GO:0005515 protein binding	IPI PMID:16446437 Abeta and tau form soluble complexes that may promote self a...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:16446437 Abeta and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer's disease.
GO:0005515 protein binding	IPI PMID:16480949 The intracellular domain of amyloid precursor protein intera...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:16480949 The intracellular domain of amyloid precursor protein interacts with flotillin-1, a lipid raft protein.
GO:0005515 protein binding	IPI PMID:16554819 The prolyl isomerase Pin1 regulates amyloid precursor protei...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:16554819 The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production.
GO:0005515 protein binding	IPI PMID:17112520 Aluminum inhibits proteolytic degradation of amyloid beta pe...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:17112520 Epub 2006 Nov 9. Aluminum inhibits proteolytic degradation of amyloid beta peptide by cathepsin D: a potential link between aluminum accumulation and neuritic plaque deposition.
GO:0005515 protein binding	IPI PMID:17709753 Amyolid precursor protein mediates presynaptic localization ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:17709753 Amyolid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter.
GO:0005515 protein binding	IPI PMID:20195357 A comprehensive resource of interacting protein regions for ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:20195357 A comprehensive resource of interacting protein regions for refining human transcription factor networks.
GO:0005515 protein binding	IPI PMID:20811458 Gamma-secretase activating protein is a therapeutic target f...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:20811458 Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease.
GO:0005515 protein binding	IPI PMID:20817278 Iron-export ferroxidase activity of β-amyloid precursor prot...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:20817278 Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease.
GO:0005515 protein binding	IPI PMID:20828565 An aminopeptidase from Streptomyces sp. KK565 degrades beta ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:20828565 Epub 2010 Sep 7. An aminopeptidase from Streptomyces sp.
GO:0005515 protein binding	IPI PMID:21163940 Interactome mapping suggests new mechanistic details underly...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:21163940 Interactome mapping suggests new mechanistic details underlying Alzheimer's disease.
GO:0005515 protein binding	IPI PMID:2119582 Transforming growth factor-beta bound to soluble derivatives...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:2119582 Transforming growth factor-beta bound to soluble derivatives of the beta amyloid precursor protein of Alzheimer's disease.
GO:0005515 protein binding	IPI PMID:21293490 Mediator is a transducer of amyloid-precursor-protein-depend...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:21293490 Mediator is a transducer of amyloid-precursor-protein-dependent nuclear signalling.
GO:0005515 protein binding	IPI PMID:22730553 Open-closed motion of Mint2 regulates APP metabolism.	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:22730553 Open-closed motion of Mint2 regulates APP metabolism.
GO:0005515 protein binding	IPI PMID:22801501 A mutation in APP protects against Alzheimer's disease and a...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:22801501 A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.
GO:0005515 protein binding	IPI PMID:23585889 Generation of amyloid-β is reduced by the interaction of cal...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:23585889 Generation of amyloid-β is reduced by the interaction of calreticulin with amyloid precursor protein, presenilin and nicastrin.
GO:0005515 protein binding	IPI PMID:24028865 Impact of the cellular prion protein on amyloid-β and 3PO-ta...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:24028865 Impact of the cellular prion protein on amyloid-β and 3PO-tau processing.
GO:0005515 protein binding	IPI PMID:24284412 Amyloid beta a4 precursor protein-binding family B member 1 ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:24284412 2013 Nov 27. Amyloid beta a4 precursor protein-binding family B member 1 (FE65) interactomics revealed synaptic vesicle glycoprotein 2A (SV2A) and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) as new binding proteins in the human brain.
GO:0005515 protein binding	IPI PMID:24867889 sAPP modulates iron efflux from brain microvascular endothel...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:24867889 sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin.
GO:0005515 protein binding	IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:25241761 Oct 9. Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.
GO:0005515 protein binding	IPI PMID:25959826 Quantitative interaction proteomics of neurodegenerative dis...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:25959826 2015 May 7. Quantitative interaction proteomics of neurodegenerative disease proteins.
GO:0005515 protein binding	IPI PMID:26496610 A human interactome in three quantitative dimensions organiz...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:26496610 Oct 22. A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
GO:0005515 protein binding	IPI PMID:29423001 Hypoxia increases amyloid-β level in exosomes by enhancing t...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:29423001 Hypoxia increases amyloid-β level in exosomes by enhancing the interaction between CD147 and Hook1.
GO:0005515 protein binding	IPI PMID:29578633 Probing the Mint2 Protein-Protein Interaction Network Releva...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:29578633 Probing the Mint2 Protein-Protein Interaction Network Relevant to the Pathophysiology of Alzheimer's Disease.
GO:0005515 protein binding	IPI PMID:30086173 TMEM30A is a candidate interacting partner for the β-carboxy...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:30086173 eCollection 2018. TMEM30A is a candidate interacting partner for the β-carboxyl-terminal fragment of amyloid-β precursor protein in endosomes.
GO:0005515 protein binding	IPI PMID:30538620 Visualization of Alzheimer's Disease Related α-/β-/γ-Secreta...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:30538620 eCollection 2018. Visualization of Alzheimer's Disease Related α-/β-/γ-Secretase Ternary Complex by Bimolecular Fluorescence Complementation Based Fluorescence Resonance Energy Transfer.
GO:0005515 protein binding	IPI PMID:31413325 HENA, heterogeneous network-based data set for Alzheimer's d...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:31413325 HENA, heterogeneous network-based data set for Alzheimer's disease.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:34446781 First identification of ITM2B interactome in the human retin...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:34446781 First identification of ITM2B interactome in the human retina.
GO:0005515 protein binding	IPI PMID:35063084 Tau interactome maps synaptic and mitochondrial processes as...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:35063084 2022 Jan 20. Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration.
GO:0005515 protein binding	IPI PMID:35914814 Chr21 protein-protein interactions: enrichment in proteins i...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:35914814 Chr21 protein-protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer's disease.
GO:0005515 protein binding	IPI PMID:35922511 A physical wiring diagram for the human immune system.	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:35922511 Aug 3. A physical wiring diagram for the human immune system.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:40205054 Apr 9. Multimodal cell maps as a foundation for structural and functional genomics.
GO:0005515 protein binding	IPI PMID:8855266 Association of a novel human FE65-like protein with the cyto...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:8855266 Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein.
GO:0005515 protein binding	IPI PMID:8887653 The phosphotyrosine interaction domains of X11 and FE65 bind...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:8887653 The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein.
GO:0005515 protein binding	IPI PMID:9223340 Interaction between amyloid precursor protein and presenilin...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:9223340 Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease.
GO:0005515 protein binding	IPI PMID:9338779 An intracellular protein that binds amyloid-beta peptide and...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:9338779 An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer's disease.
GO:0005515 protein binding	IPI PMID:9461550 Fe65L2: a new member of the Fe65 protein family interacting ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:9461550 Fe65L2: a new member of the Fe65 protein family interacting with the intracellular domain of the Alzheimer's beta-amyloid precursor protein.
GO:0005515 protein binding	IPI PMID:10673326 Agrin binds to beta-amyloid (Abeta), accelerates abeta fibri...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:10673326 Agrin binds to beta-amyloid (Abeta), accelerates abeta fibril formation, and is localized to Abeta deposits in Alzheimer's disease brain.
GO:0005515 protein binding	IPI PMID:11756426 Amyloid beta binds trimers as well as monomers of the 75-kDa...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:11756426 Dec 27. Amyloid beta binds trimers as well as monomers of the 75-kDa neurotrophin receptor and activates receptor signaling.
GO:0005515 protein binding	IPI PMID:15615705 CLAC binds to amyloid beta peptides through the positively c...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:15615705 2004 Dec 21. CLAC binds to amyloid beta peptides through the positively charged amino acid cluster within the collagenous domain 1 and inhibits formation of amyloid fibrils.
GO:0005515 protein binding	IPI PMID:17051221 Structures of human insulin-degrading enzyme reveal a new su...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:17051221 Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism.
GO:0005515 protein binding	IPI PMID:17116874 Blocking the apolipoprotein E/amyloid-beta interaction as a ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:17116874 Blocking the apolipoprotein E/amyloid-beta interaction as a potential therapeutic approach for Alzheimer's disease.
GO:0005515 protein binding	IPI PMID:18806802 Cyclophilin D deficiency attenuates mitochondrial and neuron...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:18806802 Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease.
GO:0005515 protein binding	IPI PMID:22179788 The extracellular chaperone clusterin sequesters oligomeric ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:22179788 The extracellular chaperone clusterin sequesters oligomeric forms of the amyloid-β(1-40) peptide.
GO:0005515 protein binding	IPI PMID:22528093 Search for amyloid-binding proteins by affinity chromatograp...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:22528093 Search for amyloid-binding proteins by affinity chromatography.
GO:0005515 protein binding	IPI PMID:24931469 Molecular basis of substrate recognition and degradation by ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:24931469 2014 Jun 12. Molecular basis of substrate recognition and degradation by human presequence protease.
GO:0005515 protein binding	IPI PMID:25643321 Structural basis for amyloidogenic peptide recognition by so...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:25643321 Feb 2. Structural basis for amyloidogenic peptide recognition by sorLA.
GO:0005515 protein binding	IPI PMID:25897080 Sequential Amyloid-β Degradation by the Matrix Metalloprotea...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:25897080 2015 Apr 20. Sequential Amyloid-β Degradation by the Matrix Metalloproteases MMP-2 and MMP-9.
GO:0005515 protein binding	IPI PMID:26618561 Direct High Affinity Interaction between Aβ42 and GSK3α Stim...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:26618561 Epub 2015 Dec 15. Direct High Affinity Interaction between Aβ42 and GSK3α Stimulates Hyperphosphorylation of Tau.
GO:0005515 protein binding	IPI PMID:30158114 TLR5 decoy receptor as a novel anti-amyloid therapeutic for ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:30158114 TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer's disease.
GO:0042802 identical protein binding	IPI PMID:16286452 Gerstmann-Sträussler-Scheinker disease amyloid protein polym...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:16286452 Nov 10. Gerstmann-Sträussler-Scheinker disease amyloid protein polymerizes according to the "dock-and-lock" model.
GO:0042802 identical protein binding	IPI PMID:18805418 In vitro perturbation of aggregation processes in beta-amylo...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:18805418 Epub 2008 Sep 19. In vitro perturbation of aggregation processes in beta-amyloid peptides: a spectroscopic study.
GO:0042802 identical protein binding	IPI PMID:19549187 Quenched hydrogen/deuterium exchange NMR characterization of...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:19549187 2009 Jun 22. Quenched hydrogen/deuterium exchange NMR characterization of amyloid-beta peptide aggregates formed in the presence of Cu2+ or Zn2+.
GO:0042802 identical protein binding	IPI PMID:19754881 The thioflavin T fluorescence assay for amyloid fibril detec...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:19754881 2009 Sep 15. The thioflavin T fluorescence assay for amyloid fibril detection can be biased by the presence of exogenous compounds.
GO:0042802 identical protein binding	IPI PMID:20573181 Progressive accumulation of amyloid-beta oligomers in Alzhei...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:20573181 2010 Jun 22. Progressive accumulation of amyloid-beta oligomers in Alzheimer's disease and in amyloid precursor protein transgenic mice is accompanied by selective alterations in synaptic scaffold proteins.
GO:0042802 identical protein binding	IPI PMID:20818335 Neurotoxicity of Alzheimer's disease Aβ peptides is induced ...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:20818335 Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio.
GO:0042802 identical protein binding	IPI PMID:21113149 Reversing EphB2 depletion rescues cognitive functions in Alz...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:21113149 Reversing EphB2 depletion rescues cognitive functions in Alzheimer model.
GO:0042802 identical protein binding	IPI PMID:21205198 Lysophosphatidylcholine modulates fibril formation of amyloi...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:21205198 2011 Jan 17. Lysophosphatidylcholine modulates fibril formation of amyloid beta peptide.
GO:0042802 identical protein binding	IPI PMID:21320494 Lipid matrix plays a role in Abeta fibril kinetics and morph...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:21320494 2011 Feb 12. Lipid matrix plays a role in Abeta fibril kinetics and morphology.
GO:0042802 identical protein binding	IPI PMID:21527912 Extracellular phosphorylation of the amyloid β-peptide promo...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:21527912 Extracellular phosphorylation of the amyloid β-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease.
GO:0042802 identical protein binding	IPI PMID:22200570 Effect of N-homocysteinylation on physicochemical and cytoto...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:22200570 2011 Dec 23. Effect of N-homocysteinylation on physicochemical and cytotoxic properties of amyloid β-peptide.
GO:0042802 identical protein binding	IPI PMID:22584060 Dimeric structure of transmembrane domain of amyloid precurs...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:22584060 Epub 2012 May 11. Dimeric structure of transmembrane domain of amyloid precursor protein in micellar environment.
GO:0042802 identical protein binding	IPI PMID:23103738 A comparative analysis of the aggregation behavior of amyloi...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:23103738 Epub 2012 Oct 24. A comparative analysis of the aggregation behavior of amyloid-β peptide variants.
GO:0042802 identical protein binding	IPI PMID:23353684 Protease-activated alpha-2-macroglobulin can inhibit amyloid...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:23353684 2013 Jan 23. Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via two distinct mechanisms.
GO:0042802 identical protein binding	IPI PMID:23416305 Interaction between soluble Aβ-(1-40) monomer and Aβ-(1-42) ...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:23416305 2013 Feb 15. Interaction between soluble Aβ-(1-40) monomer and Aβ-(1-42) fibrils probed by paramagnetic relaxation enhancement.
GO:0042802 identical protein binding	IPI PMID:23551356 N-terminal domain of Pyrococcus furiosus l-asparaginase func...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:23551356 N-terminal domain of Pyrococcus furiosus l-asparaginase functions as a non-specific, stable, molecular chaperone.
GO:0042802 identical protein binding	IPI PMID:23603391 NMR characterization of the interaction of GroEL with amyloi...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:23603391 2013 Apr 18. NMR characterization of the interaction of GroEL with amyloid β as a model ligand.
GO:0042802 identical protein binding	IPI PMID:23907009 Isobavachalcone and bavachinin from Psoraleae Fructus modula...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:23907009 Epub 2013 Jul 29. Isobavachalcone and bavachinin from Psoraleae Fructus modulate Aβ42 aggregation process through different mechanisms in vitro.
GO:0042802 identical protein binding	IPI PMID:24065130 Amyloid-β oligomers induce synaptic damage via Tau-dependent...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:24065130 Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin.
GO:0042802 identical protein binding	IPI PMID:24720730 The coexistence of an equal amount of Alzheimer's amyloid-β ...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:24720730 The coexistence of an equal amount of Alzheimer's amyloid-β 40 and 42 forms structurally stable and toxic oligomers through a distinct pathway.
GO:0042802 identical protein binding	IPI PMID:28882996 Fibril structure of amyloid-β(1-42) by cryo-electron microsc...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:28882996 Sep 7. Fibril structure of amyloid-β(1-42) by cryo-electron microscopy.
GO:0042802 identical protein binding	IPI PMID:17116874 Blocking the apolipoprotein E/amyloid-beta interaction as a ...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:17116874 Blocking the apolipoprotein E/amyloid-beta interaction as a potential therapeutic approach for Alzheimer's disease.
GO:0042802 identical protein binding	IPI PMID:18059284 Evidence of fibril-like β-sheet structures in a neurotoxic a...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:18059284 Evidence of fibril-like β-sheet structures in a neurotoxic amyloid intermediate of Alzheimer's β-amyloid.
GO:0042802 identical protein binding	IPI PMID:18483195 Paired beta-sheet structure of an Abeta(1-40) amyloid fibril...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:18483195 Paired beta-sheet structure of an Abeta(1-40) amyloid fibril revealed by electron microscopy.
GO:0042802 identical protein binding	IPI PMID:18499799 Two-dimensional infrared spectra of isotopically diluted amy...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:18499799 Two-dimensional infrared spectra of isotopically diluted amyloid fibrils from Abeta40.
GO:0042802 identical protein binding	IPI PMID:19304802 Synaptic transmission block by presynaptic injection of olig...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:19304802 Synaptic transmission block by presynaptic injection of oligomeric amyloid beta.
GO:0042802 identical protein binding	IPI PMID:19458258 Alpha-helix targeting reduces amyloid-beta peptide toxicity.	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:19458258 Alpha-helix targeting reduces amyloid-beta peptide toxicity.
GO:0042802 identical protein binding	IPI PMID:19706468 Structure-neurotoxicity relationships of amyloid beta-protei...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:19706468 Structure-neurotoxicity relationships of amyloid beta-protein oligomers.
GO:0042802 identical protein binding	IPI PMID:19706519 Measurement of amyloid fibril mass-per-length by tilted-beam...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:19706519 Measurement of amyloid fibril mass-per-length by tilted-beam transmission electron microscopy.
GO:0042802 identical protein binding	IPI PMID:19841277 Site-specific modification of Alzheimer's peptides by choles...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:19841277 Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity.
GO:0042802 identical protein binding	IPI PMID:20133839 Mechanism of amyloid plaque formation suggests an intracellu...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:20133839 Mechanism of amyloid plaque formation suggests an intracellular basis of Abeta pathogenicity.
GO:0042802 identical protein binding	IPI PMID:22036569 Arc/Arg3.1 regulates an endosomal pathway essential for acti...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:22036569 Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent β-amyloid generation.
GO:0042802 identical protein binding	IPI PMID:22179788 The extracellular chaperone clusterin sequesters oligomeric ...	ACCEPT	Summary: Abeta self-associates forming dimers and higher oligomers. Reason: Direct single-molecule fluorescence demonstration of Abeta oligomerization. Supporting Evidence: PMID:22179788 Aβ(1-40) forms a heterogeneous distribution of small oligomers (from dimers to 50-mers)
GO:0042802 identical protein binding	IPI PMID:25543257 Modeling an in-register, parallel "iowa" aβ fibril structure...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:25543257 Dec 24. Modeling an in-register, parallel "iowa" aβ fibril structure using solid-state NMR data from labeled samples with rosetta.
GO:0042802 identical protein binding	IPI PMID:30158114 TLR5 decoy receptor as a novel anti-amyloid therapeutic for ...	ACCEPT	Summary: IPI annotation. APP dimerization (homodimerization) is well-established and functionally relevant for cell adhesion and processing. Reason: APP homodimerization is a core function. More informative than generic protein binding. Supporting Evidence: PMID:30158114 TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer's disease.
GO:0005615 extracellular space	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:0006816 calcium ion transport	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA annotation for calcium ion transport. APP is not a calcium transporter. Abeta peptides can form calcium-permeable pores in membranes and Abeta oligomers disrupt calcium homeostasis, but APP itself does not transport calcium. This is an indirect effect of cleavage products. Reason: APP is not a calcium transporter. The calcium effects are indirect, mediated by Abeta pore formation and signaling disruption. Over-annotation.
GO:0007611 learning or memory	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation for learning or memory. APP and its cleavage products (especially Abeta oligomers) affect learning and memory, but this is a downstream phenotypic consequence of APP processing rather than a core molecular function. Reason: learning or memory is a downstream consequence of APP/Abeta biology. Important for disease relevance but not a core function. Keep as non-core.
GO:0010288 response to lead ion	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation for response to lead ion. Lead exposure has been shown to increase APP expression and Abeta production, but this is a response to an environmental toxin rather than a core function. Reason: Response to lead ion is an environmental response, not a core function of APP. Keep as non-core.
GO:0016504 peptidase activator activity	IEA GO_REF:0000107	UNDECIDED	Summary: IEA annotation for peptidase activator activity. It is unclear what specific peptidase APP activates. APP is itself a substrate of multiple peptidases (alpha-, beta-, gamma-secretases) but the mechanism of direct peptidase activation is not well characterized. Reason: Unclear molecular basis for peptidase activator activity. APP is a protease substrate, not clearly a protease activator. Needs further evidence.
GO:0030424 axon	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:0036269 swimming behavior	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: ISS annotation for swimming behavior based on mouse APP knockout/transgenic studies. These behavioral phenotypes reflect pleiotropic downstream effects of APP loss or Abeta overexpression in mice rather than a core molecular function of APP. Reason: Behavioral phenotype (swimming behavior) observed in mouse models. Not a core function of APP but a downstream consequence. Keep as non-core.
GO:0043523 regulation of neuron apoptotic process	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:0044304 main axon	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:0045471 response to ethanol	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:0051247 positive regulation of protein metabolic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA annotation for positive regulation of protein metabolic process. Very broad term that does not provide useful information about APP function. Reason: Too broad to be informative. Over-annotation.
GO:0070555 response to interleukin-1	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:0070851 growth factor receptor binding	IEA GO_REF:0000107	UNDECIDED	Summary: IEA annotation for growth factor receptor binding. The specific growth factor receptor that APP binds is unclear. sAPPalpha has growth factor-like properties but the receptor is not well defined. Reason: Unclear which growth factor receptor APP binds. Needs further evidence.
GO:0071280 cellular response to copper ion	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:0071287 cellular response to manganese ion	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:0071320 cellular response to cAMP	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:0071874 cellular response to norepinephrine stimulus	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:0097449 astrocyte projection	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:0098992 neuronal dense core vesicle	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:0110088 hippocampal neuron apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation for hippocampal neuron apoptotic process. This is an overly specific term for Abeta-mediated neurotoxicity. The neurotoxic effect of Abeta is well established but this is a pathological consequence, not a core function of APP. Reason: Pathological consequence of Abeta accumulation, not a core function. Overly specific cell-type qualification. Keep as non-core.
GO:1990090 cellular response to nerve growth factor stimulus	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:1990418 response to insulin-like growth factor stimulus	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:1990761 growth cone lamellipodium	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:1990812 growth cone filopodium	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation based on electronic inference. Consistent with APP biology. Reason: IEA annotation consistent with known APP functions.
GO:0005794 Golgi apparatus	IDA GO_REF:0000052	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence.
GO:0005615 extracellular space	NAS P05067-PRO_0000000093 PMID:18568035 Amyloid-beta protein dimers isolated directly from Alzheimer...	ACCEPT	Summary: NAS annotation for Abeta localization in extracellular space. Shankar et al. (2008) extracted soluble Abeta oligomers from AD brain cortex, demonstrating extracellular presence. Reason: Annotation correctly targets Abeta cleavage product (PRO_0000000093) and extracellular localization is supported by extraction from brain tissue. Supporting Evidence: PMID:18568035 We extracted soluble amyloid-beta protein (Abeta) oligomers directly from the cerebral cortex of subjects with Alzheimer's disease.
GO:0005886 plasma membrane	NAS P05067-PRO_0000000093 PMID:18568035 Amyloid-beta protein dimers isolated directly from Alzheimer...	ACCEPT	Summary: NAS annotation for Abeta at plasma membrane. Abeta oligomers act at synaptic sites, consistent with membrane association. Reason: Annotation correctly targets Abeta cleavage product. Membrane association implied by synaptic site of action, consistent with other evidence for plasma membrane localization. Supporting Evidence: PMID:18568035 The oligomers potently inhibited long-term potentiation (LTP), enhanced long-term depression (LTD) and reduced dendritic spine density in normal rodent hippocampus.
GO:0043408 regulation of MAPK cascade	ISS GO_REF:0000114	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0045666 positive regulation of neuron differentiation	ISS GO_REF:0000114	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:1900272 negative regulation of long-term synaptic potentiation	IDA P05067-PRO_0000000093 PMID:18568035 Amyloid-beta protein dimers isolated directly from Alzheimer...	ACCEPT	Summary: IDA annotation for Abeta-mediated LTP inhibition. Shankar et al. (2008) demonstrated that Abeta oligomers extracted directly from AD brains potently inhibited LTP in rodent hippocampus. Crucially, this effect was specifically attributable to Abeta DIMERS, not monomers or higher-order aggregates. Reason: Well-supported IDA annotation correctly targeting Abeta cleavage product. This is a core synaptotoxic function of Abeta dimers. Supporting Evidence: PMID:18568035 The oligomers potently inhibited long-term potentiation (LTP), enhanced long-term depression (LTD) and reduced dendritic spine density in normal rodent hippocampus
GO:1900272 negative regulation of long-term synaptic potentiation	NAS PMID:19242475 Cellular prion protein mediates impairment of synaptic plast...	ACCEPT	Summary: NAS annotation based on author statement. Reason: NAS annotation supported by literature. Supporting Evidence: PMID:19242475 Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers.
GO:1900454 positive regulation of long-term synaptic depression	IDA P05067-PRO_0000000093 PMID:18568035 Amyloid-beta protein dimers isolated directly from Alzheimer...	ACCEPT	Summary: IDA annotation for Abeta-mediated LTD enhancement. Shankar et al. (2008) showed that Abeta dimers from AD brains enhanced LTD in rodent hippocampus. The mechanism requires metabotropic glutamate receptors (mGluRs). Reason: Well-supported IDA annotation correctly targeting Abeta cleavage product. LTD enhancement is a core synaptotoxic function of Abeta dimers. Supporting Evidence: PMID:18568035 The oligomers potently inhibited long-term potentiation (LTP), enhanced long-term depression (LTD) and reduced dendritic spine density in normal rodent hippocampus
GO:1900454 positive regulation of long-term synaptic depression	NAS PMID:19242475 Cellular prion protein mediates impairment of synaptic plast...	ACCEPT	Summary: NAS annotation based on author statement. Reason: NAS annotation supported by literature. Supporting Evidence: PMID:19242475 Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers.
GO:1902951 negative regulation of dendritic spine maintenance	IDA P05067-PRO_0000000093 PMID:18568035 Amyloid-beta protein dimers isolated directly from Alzheimer...	ACCEPT	Summary: IDA annotation for Abeta-mediated spine loss. Shankar et al. (2008) showed that Abeta oligomers from AD brains reduced dendritic spine density. Effects specifically attributable to Abeta dimers and require NMDA receptors. Reason: Well-supported IDA annotation correctly targeting Abeta cleavage product. Spine loss is a core synaptotoxic function of Abeta dimers. Supporting Evidence: PMID:18568035 The oligomers potently inhibited long-term potentiation (LTP), enhanced long-term depression (LTD) and reduced dendritic spine density in normal rodent hippocampus
GO:1902951 negative regulation of dendritic spine maintenance	NAS PMID:22820466 Alzheimer amyloid-β oligomer bound to postsynaptic prion pro...	ACCEPT	Summary: NAS annotation based on author statement. Reason: NAS annotation supported by literature. Supporting Evidence: PMID:22820466 Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons.
GO:0043525 positive regulation of neuron apoptotic process	IGI PMID:23164821 Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of neuron apoptotic process. Abeta and gamma-CTF fragments promote neuronal apoptosis, but this is a pathological consequence of aberrant APP processing rather than a core physiological function. Reason: Neurotoxicity is a pathological consequence of Abeta, not a core APP function. Keep as non-core. Supporting Evidence: PMID:23164821 silencing of DKK1 blocks Aβ neurotoxicity
GO:0032224 positive regulation of synaptic transmission, cholinergic	IDA PMID:33239400 Implications of Oligomeric Amyloid-Beta (oAβ(42)) Signaling ...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:33239400 oAβ42 activates both homomeric α7- and heteromeric α7β2-nAChR subtypes while preferentially enhancing α7β2-nAChR open-dwell times
GO:0043083 synaptic cleft	TAS PMID:33239400 Implications of Oligomeric Amyloid-Beta (oAβ(42)) Signaling ...	ACCEPT	Summary: TAS annotation based on author statement in referenced publication. Reason: TAS annotation supported by literature. Supporting Evidence: PMID:33239400 the oligomeric form of amyloid-β (oAβ42), interacting with α7-containing nicotinic acetylcholine receptor (nAChR) subtypes
GO:0048018 receptor ligand activity	IDA PMID:33239400 Implications of Oligomeric Amyloid-Beta (oAβ(42)) Signaling ...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:33239400 these data provide a molecular mechanism supporting a role for α7β2-nAChR in mediating the effects of oAβ42
GO:0106003 amyloid-beta complex	IDA PMID:33239400 Implications of Oligomeric Amyloid-Beta (oAβ(42)) Signaling ...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:33239400 the oligomeric form of amyloid-β (oAβ42)
GO:0031901 early endosome membrane	IDA PMID:16174740 Neuronal sorting protein-related receptor sorLA/LR11 regulat...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:16174740 Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein.
GO:0048018 receptor ligand activity	IDA PMID:16174740 Neuronal sorting protein-related receptor sorLA/LR11 regulat...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:16174740 Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein.
GO:1904646 cellular response to amyloid-beta	IDA PMID:29518356 TREM2 Is a Receptor for β-Amyloid that Mediates Microglial F...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:29518356 TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function.
GO:1905606 regulation of presynapse assembly	IMP PMID:19726636 Presynaptic and postsynaptic interaction of the amyloid prec...	ACCEPT	Summary: IMP annotation based on mutant phenotype analysis. Reason: IMP annotation supported by mutant phenotype data. Supporting Evidence: PMID:19726636 Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis.
GO:1905606 regulation of presynapse assembly	IDA PMID:19726636 Presynaptic and postsynaptic interaction of the amyloid prec...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:19726636 Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis.
GO:0030425 dendrite	IDA PMID:24012003 Metabotropic glutamate receptor 5 is a coreceptor for Alzhei...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:24012003 Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein.
GO:0120283 protein serine/threonine kinase binding	IPI PMID:24305806 Pharmacologic inhibition of ROCK2 suppresses amyloid-β produ...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:24305806 Pharmacologic inhibition of ROCK2 suppresses amyloid-β production in an Alzheimer's disease mouse model.
GO:0055096 low-density lipoprotein particle mediated signaling	IDA PMID:26005850 Central role for PICALM in amyloid-β blood-brain barrier tra...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:26005850 PICALM regulated PICALM/clathrin-dependent internalization of Aβ bound to the low density lipoprotein receptor related protein-1
GO:0098989 NMDA selective glutamate receptor signaling pathway	TAS PMID:17360908 Natural oligomers of the Alzheimer amyloid-beta protein indu...	ACCEPT	Summary: TAS annotation based on author statement in referenced publication. Reason: TAS annotation supported by literature. Supporting Evidence: PMID:17360908 Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway.
GO:1902993 positive regulation of amyloid precursor protein catabolic process	IGI PMID:22406537 A multimodal RAGE-specific inhibitor reduces amyloid β-media...	ACCEPT	Summary: RAGE-mediated Abeta signaling affects APP processing through beta-secretase activity. Reason: Study shows RAGE inhibitor reduced beta-secretase activity and Abeta production. Supporting Evidence: PMID:22406537 In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response
GO:0050850 positive regulation of calcium-mediated signaling	IGI PMID:22500019 Amyloid β (Aβ) peptide directly activates amylin-3 receptor ...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of calcium-mediated signaling. Abeta disrupts calcium homeostasis. Downstream pathological effect. Reason: Calcium signaling disruption is a downstream effect of Abeta. Keep as non-core. Supporting Evidence: PMID:22500019 2012 Apr 12. Amyloid β (Aβ) peptide directly activates amylin-3 receptor subtype by triggering multiple intracellular signaling pathways.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9839072	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005829 cytosol	TAS Reactome:R-HSA-9839072	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0010628 positive regulation of gene expression	IMP PMID:15457210 RAGE potentiates Abeta-induced perturbation of neuronal func...	KEEP AS NON CORE	Summary: IMP annotation for positive regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: positive regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:15457210 Double Tgs (mutant APP (mAPP)/RAGE) displayed early abnormalities in spatial learning/memory, accompanied by altered activation of markers of synaptic plasticity and exaggerated neuropathologic findings, before such changes were found in mAPP mice
GO:1900272 negative regulation of long-term synaptic potentiation	IGI PMID:15457210 RAGE potentiates Abeta-induced perturbation of neuronal func...	MARK AS OVER ANNOTATED	Summary: IGI annotation from RAGE interaction study. Arancio et al. (2004) showed mAPP/RAGE double transgenics have early LTP deficits, but RAGE is the receptor mediating Abeta effects. The annotation is technically valid but the mechanism is RAGE-dependent. Reason: While LTP inhibition occurs in mAPP transgenics, this paper demonstrates it is RAGE-mediated. The annotation should ideally be on Abeta (PRO_0000000093) not full APP, and notes RAGE dependency. Supporting Evidence: PMID:15457210 RAGE is a cofactor for Abeta-induced neuronal perturbation in a model of Alzheimer's-type pathology
GO:1901224 positive regulation of non-canonical NF-kappaB signal transduction	IGI PMID:15457210 RAGE potentiates Abeta-induced perturbation of neuronal func...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of non-canonical NF-kappaB signal transduction. Abeta-mediated inflammatory signaling. Downstream effect. Reason: NF-kappaB activation is a downstream inflammatory effect of Abeta. Keep as non-core. Supporting Evidence: PMID:15457210 Receptor for Advanced Glycation Endproducts (RAGE), a multiligand receptor in the immunoglobulin superfamily, functions as a signal-transducing cell surface acceptor for amyloid-beta peptide (Abeta)
GO:2000406 positive regulation of T cell migration	IMP PMID:19660551 Biochemical and immunohistochemical analysis of an Alzheimer...	KEEP AS NON CORE	Summary: IMP annotation for positive regulation of T cell migration. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (positive regulation of T cell migration) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:19660551 2009 Aug 4. Biochemical and immunohistochemical analysis of an Alzheimer's disease mouse model reveals the presence of multiple cerebral Abeta assembly forms throughout life.
GO:0007611 learning or memory	IGI PMID:20164328 Loss of alpha7 nicotinic receptors enhances beta-amyloid oli...	KEEP AS NON CORE	Summary: IGI annotation for learning or memory. APP and its cleavage products (especially Abeta oligomers) affect learning and memory, but this is a downstream phenotypic consequence of APP processing rather than a core molecular function. Reason: learning or memory is a downstream consequence of APP/Abeta biology. Important for disease relevance but not a core function. Keep as non-core. Supporting Evidence: PMID:20164328 Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease.
GO:0010468 regulation of gene expression	IGI PMID:21857966 WNT5A signaling contributes to Aβ-induced neuroinflammation ...	KEEP AS NON CORE	Summary: IGI annotation for regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:21857966 WNT5A signaling contributes to Aβ-induced neuroinflammation and neurotoxicity.
GO:0030111 regulation of Wnt signaling pathway	IC PMID:21857966 WNT5A signaling contributes to Aβ-induced neuroinflammation ...	KEEP AS NON CORE	Summary: IC annotation for regulation of Wnt signaling pathway. APP has been reported to interact with Wnt pathway components. Not a core function. Reason: Wnt signaling regulation is not a core function of APP. Keep as non-core. Supporting Evidence: PMID:21857966 WNT5A signaling contributes to Aβ-induced neuroinflammation and neurotoxicity.
GO:0046330 positive regulation of JNK cascade	IGI PMID:23921129 FcγRIIb mediates amyloid-β neurotoxicity and memory impairme...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of JNK cascade. APP cytoplasmic domain interacts with JIP1 and can activate JNK signaling. Downstream signaling effect. Reason: JNK cascade activation is a downstream signaling effect. Keep as non-core. Supporting Evidence: PMID:23921129 Neuronal FcγRIIb activated ER stress and caspase-12
GO:0048169 regulation of long-term neuronal synaptic plasticity	IGI PMID:23921129 FcγRIIb mediates amyloid-β neurotoxicity and memory impairme...	ACCEPT	Summary: IGI annotation based on genetic interaction evidence. NOTE: Many IGI annotations for APP involve Abeta-specific effects from transgenic mouse studies and may not represent full-length APP function. Reason: IGI annotation supported by genetic interaction data. Note potential cleavage product specificity. Supporting Evidence: PMID:23921129 Fcgr2b deficiency ameliorated Aβ-induced inhibition of long-term potentiation
GO:0007611 learning or memory	IGI PMID:20445063 Memory impairment in transgenic Alzheimer mice requires cell...	KEEP AS NON CORE	Summary: IGI annotation for learning or memory. APP and its cleavage products (especially Abeta oligomers) affect learning and memory, but this is a downstream phenotypic consequence of APP processing rather than a core molecular function. Reason: learning or memory is a downstream consequence of APP/Abeta biology. Important for disease relevance but not a core function. Keep as non-core. Supporting Evidence: PMID:20445063 Memory impairment in transgenic Alzheimer mice requires cellular prion protein.
GO:0007611 learning or memory	IGI PMID:24012003 Metabotropic glutamate receptor 5 is a coreceptor for Alzhei...	KEEP AS NON CORE	Summary: IGI annotation for learning or memory. APP and its cleavage products (especially Abeta oligomers) affect learning and memory, but this is a downstream phenotypic consequence of APP processing rather than a core molecular function. Reason: learning or memory is a downstream consequence of APP/Abeta biology. Important for disease relevance but not a core function. Keep as non-core. Supporting Evidence: PMID:24012003 Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein.
GO:0010628 positive regulation of gene expression	IGI PMID:28008308 The Protective Role of microRNA-200c in Alzheimer's Disease ...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: positive regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:28008308 eCollection 2016. The Protective Role of microRNA-200c in Alzheimer's Disease Pathologies Is Induced by Beta Amyloid-Triggered Endoplasmic Reticulum Stress.
GO:0010629 negative regulation of gene expression	IGI PMID:28008308 The Protective Role of microRNA-200c in Alzheimer's Disease ...	KEEP AS NON CORE	Summary: IGI annotation for negative regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: negative regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:28008308 eCollection 2016. The Protective Role of microRNA-200c in Alzheimer's Disease Pathologies Is Induced by Beta Amyloid-Triggered Endoplasmic Reticulum Stress.
GO:0046982 protein heterodimerization activity	IPI PMID:19660551 Biochemical and immunohistochemical analysis of an Alzheimer...	ACCEPT	Summary: Abeta forms SDS-stable dimers in J20 transgenic mouse brain. Reason: Direct biochemical demonstration of Abeta dimerization. Supporting Evidence: PMID:19660551 Using an immunoprecipitation/Western blotting technique we find an age-dependent increase in Abeta monomer and SDS-stable dimer
GO:0050808 synapse organization	IGI PMID:24012003 Metabotropic glutamate receptor 5 is a coreceptor for Alzhei...	ACCEPT	Summary: IGI annotation based on genetic interaction evidence. NOTE: Many IGI annotations for APP involve Abeta-specific effects from transgenic mouse studies and may not represent full-length APP function. Reason: IGI annotation supported by genetic interaction data. Note potential cleavage product specificity. Supporting Evidence: PMID:24012003 Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein.
GO:0051247 positive regulation of protein metabolic process	IMP PMID:11404397 Beta-amyloid activates the mitogen-activated protein kinase ...	ACCEPT	Summary: IMP annotation based on mutant phenotype analysis. Reason: IMP annotation supported by mutant phenotype data. Supporting Evidence: PMID:11404397 Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer's disease.
GO:0051262 protein tetramerization	IPI PMID:19660551 Biochemical and immunohistochemical analysis of an Alzheimer...	ACCEPT	Summary: Abeta forms multiple assembly forms including oligomers in J20 mouse brain. Reason: Study shows multiple Abeta assembly forms detected biochemically. Supporting Evidence: PMID:19660551 These data demonstrate the presence of multiple assembly forms of Abeta throughout the life of J20 mice
GO:0070206 protein trimerization	IPI PMID:19660551 Biochemical and immunohistochemical analysis of an Alzheimer...	ACCEPT	Summary: Abeta forms multiple oligomeric assembly forms in J20 mouse brain. Reason: Study demonstrates multiple Abeta assembly forms including oligomers. Supporting Evidence: PMID:19660551 These data demonstrate the presence of multiple assembly forms of Abeta throughout the life of J20 mice
GO:0150003 regulation of spontaneous synaptic transmission	IGI PMID:15457210 RAGE potentiates Abeta-induced perturbation of neuronal func...	ACCEPT	Summary: Abeta-RAGE interaction affects synaptic plasticity markers in transgenic mouse models. Reason: Study shows RAGE-mediated Abeta effects on synaptic function. Supporting Evidence: PMID:15457210 Double Tgs (mutant APP (mAPP)/RAGE) displayed early abnormalities in spatial learning/memory, accompanied by altered activation of markers of synaptic plasticity and exaggerated neuropathologic findings, before such changes were found in mAPP mice
GO:1905908 positive regulation of amyloid fibril formation	IMP PMID:19660551 Biochemical and immunohistochemical analysis of an Alzheimer...	KEEP AS NON CORE	Summary: IMP annotation for positive regulation of amyloid fibril formation. While amyloid fibril formation is central to AD pathology, it is a pathological process rather than a core physiological function. Reason: Amyloid fibril formation is pathological rather than a core physiological function. Keep as non-core. Supporting Evidence: PMID:19660551 biochemical fractionation and ELISA analysis revealed evidence of TBS and triton-insoluble sedimentable Abeta aggregates at the earliest ages studied
GO:0034361 very-low-density lipoprotein particle	IPI PMID:9211985 Association of human, rat, and rabbit apolipoprotein E with ...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:9211985 when equivalent amounts of apoE3 or E4 were incubated with beta-amyloid (A beta), apoE3 formed 20 times as much SDS-stable complex with the peptide as apoE4
GO:0034362 low-density lipoprotein particle	IPI PMID:9211985 Association of human, rat, and rabbit apolipoprotein E with ...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:9211985 Lipoproteins isolated from the plasma of individuals homozygous for either epsilon2 or epsilon3 were incubated with A beta(1-40)
GO:0034363 intermediate-density lipoprotein particle	IPI PMID:9211985 Association of human, rat, and rabbit apolipoprotein E with ...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:9211985 lipoprotein-associated rabbit apoE (Cys112, Arg158) did bind the peptide
GO:0034364 high-density lipoprotein particle	IPI PMID:9211985 Association of human, rat, and rabbit apolipoprotein E with ...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:9211985 ApoE2:A beta complex formation was comparable to apoE3:A beta in both native and purified preparations of apoE
GO:0042803 protein homodimerization activity	IPI PMID:15447668 MAPK recruitment by beta-amyloid in organotypic hippocampal ...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:15447668 MAPK recruitment by beta-amyloid in organotypic hippocampal slice cultures depends on physical state and exposure time.
GO:0042803 protein homodimerization activity	IPI PMID:22179788 The extracellular chaperone clusterin sequesters oligomeric ...	ACCEPT	Summary: Abeta forms dimers as part of its oligomerization pathway. Reason: Single-molecule fluorescence shows Abeta forms dimers to 50-mers. Supporting Evidence: PMID:22179788 Aβ(1-40) forms a heterogeneous distribution of small oligomers (from dimers to 50-mers)
GO:0051260 protein homooligomerization	IPI PMID:15447668 MAPK recruitment by beta-amyloid in organotypic hippocampal ...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:15447668 MAPK recruitment by beta-amyloid in organotypic hippocampal slice cultures depends on physical state and exposure time.
GO:0051260 protein homooligomerization	IPI PMID:18602473 Aggregation and catabolism of disease-associated intra-Abeta...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:18602473 2008 Jun 17. Aggregation and catabolism of disease-associated intra-Abeta mutations: reduced proteolysis of AbetaA21G by neprilysin.
GO:0051260 protein homooligomerization	IPI PMID:22179788 The extracellular chaperone clusterin sequesters oligomeric ...	ACCEPT	Summary: Abeta self-associates forming a range of oligomeric species from dimers to 50-mers. Reason: Direct single-molecule fluorescence characterization of Abeta oligomerization. Supporting Evidence: PMID:22179788 Aβ(1-40) forms a heterogeneous distribution of small oligomers (from dimers to 50-mers)
GO:0010628 positive regulation of gene expression	IGI PMID:23164821 Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: positive regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:23164821 Aβ induces the neuronal expression of the canonical wnt antagonist, Dickkopf-1 (Dkk1)
GO:1904591 positive regulation of protein import	IDA PMID:23164821 Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:23164821 We demonstrate that Aβ rapidly targets the clusterin protein, causing its intracellular accumulation possibly by blocking its exit from neurons
GO:1990000 amyloid fibril formation	EXP PMID:26138908 High-resolution NMR characterization of low abundance oligom...	ACCEPT	Summary: EXP annotation based on experimental evidence. Reason: EXP annotation supported by direct experimental data. Supporting Evidence: PMID:26138908 High-resolution NMR characterization of low abundance oligomers of amyloid-β without purification.
GO:1990000 amyloid fibril formation	EXP PMID:9737846 Solution structure of methionine-oxidized amyloid beta-pepti...	ACCEPT	Summary: EXP annotation based on experimental evidence. Reason: EXP annotation supported by direct experimental data. Supporting Evidence: PMID:9737846 Solution structure of methionine-oxidized amyloid beta-peptide (1-40).
GO:0007611 learning or memory	IMP PMID:11880515 The relationship between Abeta and memory in the Tg2576 mous...	KEEP AS NON CORE	Summary: IMP annotation for learning or memory. APP and its cleavage products (especially Abeta oligomers) affect learning and memory, but this is a downstream phenotypic consequence of APP processing rather than a core molecular function. Reason: learning or memory is a downstream consequence of APP/Abeta biology. Important for disease relevance but not a core function. Keep as non-core. Supporting Evidence: PMID:11880515 The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease.
GO:0007612 learning	IMP PMID:11140684 A learning deficit related to age and beta-amyloid plaques i...	KEEP AS NON CORE	Summary: IMP annotation for learning. APP and its cleavage products (especially Abeta oligomers) affect learning and memory, but this is a downstream phenotypic consequence of APP processing rather than a core molecular function. Reason: learning is a downstream consequence of APP/Abeta biology. Important for disease relevance but not a core function. Keep as non-core. Supporting Evidence: PMID:11140684 A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease.
GO:0005515 protein binding	IPI PMID:14527950 Generation of the beta-amyloid peptide and the amyloid precu...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:14527950 2003 Oct 3. Generation of the beta-amyloid peptide and the amyloid precursor protein C-terminal fragment gamma are potentiated by FE65L1.
GO:0005769 early endosome	IDA PMID:14527950 Generation of the beta-amyloid peptide and the amyloid precu...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:14527950 2003 Oct 3. Generation of the beta-amyloid peptide and the amyloid precursor protein C-terminal fragment gamma are potentiated by FE65L1.
GO:0005783 endoplasmic reticulum	IDA PMID:14527950 Generation of the beta-amyloid peptide and the amyloid precu...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:14527950 2003 Oct 3. Generation of the beta-amyloid peptide and the amyloid precursor protein C-terminal fragment gamma are potentiated by FE65L1.
GO:0005794 Golgi apparatus	IDA PMID:14527950 Generation of the beta-amyloid peptide and the amyloid precu...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:14527950 2003 Oct 3. Generation of the beta-amyloid peptide and the amyloid precursor protein C-terminal fragment gamma are potentiated by FE65L1.
GO:0005615 extracellular space	IDA PMID:29518356 TREM2 Is a Receptor for β-Amyloid that Mediates Microglial F...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:29518356 TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function.
GO:0048018 receptor ligand activity	IDA PMID:29518356 TREM2 Is a Receptor for β-Amyloid that Mediates Microglial F...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:29518356 TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function.
GO:0014005 microglia development	IGI PMID:22198949 TLR2 is a primary receptor for Alzheimer's amyloid β peptide...	KEEP AS NON CORE	Summary: IGI annotation for microglia development. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (microglia development) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:22198949 Microglia activated by extracellularly deposited amyloid β peptide (Aβ) act as a two-edged sword in Alzheimer's disease pathogenesis
GO:0032760 positive regulation of tumor necrosis factor production	IGI PMID:22198949 TLR2 is a primary receptor for Alzheimer's amyloid β peptide...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of tumor necrosis factor production. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (positive regulation of tumor necrosis factor production) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:22198949 they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation)
GO:0005515 protein binding	IPI PMID:12054541 A secreted form of human ADAM9 has an alpha-secretase activi...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:12054541 A secreted form of human ADAM9 has an alpha-secretase activity for APP.
GO:0005515 protein binding	IPI PMID:9774383 Evidence that tumor necrosis factor alpha converting enzyme ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:9774383 Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor.
GO:0019899 enzyme binding	IPI PMID:17112471 ADAM19 is tightly associated with constitutive Alzheimer's d...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:17112471 ADAM19 is tightly associated with constitutive Alzheimer's disease APP alpha-secretase in A172 cells.
GO:0050729 positive regulation of inflammatory response	IMP PMID:29961672 miR-15b reduces amyloid-β accumulation in SH-SY5Y cell line ...	KEEP AS NON CORE	Summary: IMP annotation for positive regulation of inflammatory response. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (positive regulation of inflammatory response) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:29961672 2018 Dec 21. miR-15b reduces amyloid-β accumulation in SH-SY5Y cell line through targetting NF-κB signaling and BACE1.
GO:1901224 positive regulation of non-canonical NF-kappaB signal transduction	IMP PMID:29961672 miR-15b reduces amyloid-β accumulation in SH-SY5Y cell line ...	KEEP AS NON CORE	Summary: IMP annotation for positive regulation of non-canonical NF-kappaB signal transduction. Abeta-mediated inflammatory signaling. Downstream effect. Reason: NF-kappaB activation is a downstream inflammatory effect of Abeta. Keep as non-core. Supporting Evidence: PMID:29961672 2018 Dec 21. miR-15b reduces amyloid-β accumulation in SH-SY5Y cell line through targetting NF-κB signaling and BACE1.
GO:0010468 regulation of gene expression	IMP PMID:29274751 Reduced expression of Na(+)/Ca(2+) exchangers is associated ...	KEEP AS NON CORE	Summary: IMP annotation for regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:29274751 Reduced expression of Na(+)/Ca(2+) exchangers is associated with cognitive deficits seen in Alzheimer's disease model mice.
GO:0005515 protein binding	IPI PMID:23973487 Two β-strands of RAGE participate in the recognition and tra...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:23973487 Two β-strands of RAGE participate in the recognition and transport of amyloid-β peptide across the blood brain barrier.
GO:0010468 regulation of gene expression	IGI PMID:26200696 Dual pathways mediate β-amyloid stimulated glutathione relea...	KEEP AS NON CORE	Summary: IGI annotation for regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:26200696 Dual pathways mediate β-amyloid stimulated glutathione release from astrocytes.
GO:0010628 positive regulation of gene expression	IDA PMID:26006083 The multidrug resistance pump ABCB1 is a substrate for the u...	KEEP AS NON CORE	Summary: IDA annotation for positive regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: positive regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:26006083 2015 May 26. The multidrug resistance pump ABCB1 is a substrate for the ubiquitin ligase NEDD4-1.
GO:0010629 negative regulation of gene expression	IDA PMID:26006083 The multidrug resistance pump ABCB1 is a substrate for the u...	KEEP AS NON CORE	Summary: IDA annotation for negative regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: negative regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:26006083 2015 May 26. The multidrug resistance pump ABCB1 is a substrate for the ubiquitin ligase NEDD4-1.
GO:0106003 amyloid-beta complex	TAS PMID:22500019 Amyloid β (Aβ) peptide directly activates amylin-3 receptor ...	ACCEPT	Summary: TAS annotation based on author statement in referenced publication. Reason: TAS annotation supported by literature. Supporting Evidence: PMID:22500019 2012 Apr 12. Amyloid β (Aβ) peptide directly activates amylin-3 receptor subtype by triggering multiple intracellular signaling pathways.
GO:0005886 plasma membrane	IDA PMID:28164773 Apolipoprotein E-mediated Modulation of ADAM10 in Alzheimer'...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:28164773 Apolipoprotein E-mediated Modulation of ADAM10 in Alzheimer's Disease.
GO:0001774 microglial cell activation	IGI PMID:15457210 RAGE potentiates Abeta-induced perturbation of neuronal func...	KEEP AS NON CORE	Summary: IGI annotation for microglial cell activation. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (microglial cell activation) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:15457210 RAGE is a cofactor for Abeta-induced neuronal perturbation in a model of Alzheimer's-type pathology
GO:0001774 microglial cell activation	IGI PMID:22406537 A multimodal RAGE-specific inhibitor reduces amyloid β-media...	KEEP AS NON CORE	Summary: IGI annotation for microglial cell activation. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (microglial cell activation) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:22406537 A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease.
GO:0048143 astrocyte activation	IGI PMID:15457210 RAGE potentiates Abeta-induced perturbation of neuronal func...	KEEP AS NON CORE	Summary: IGI annotation for astrocyte activation. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (astrocyte activation) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:15457210 RAGE is a cofactor for Abeta-induced neuronal perturbation in a model of Alzheimer's-type pathology
GO:0032729 positive regulation of type II interferon production	IGI PMID:17255335 Interferon-gamma and tumor necrosis factor-alpha regulate am...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of type II interferon production. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (positive regulation of type II interferon production) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:17255335 Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice.
GO:0005886 plasma membrane	IDA PMID:28855300 An Alzheimer-associated TREM2 variant occurs at the ADAM cle...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:28855300 An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function.
GO:0010628 positive regulation of gene expression	IGI PMID:29061364 Inflammatory microglia are glycolytic and iron retentive and...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: positive regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:29061364 genotype-related increases in glycolysis, accompanied by increased PFKFB3, and an increase in the expression of ferritin
GO:0010629 negative regulation of gene expression	IGI PMID:29061364 Inflammatory microglia are glycolytic and iron retentive and...	KEEP AS NON CORE	Summary: IGI annotation for negative regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: negative regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:29061364 microglia prepared from wildtype mice and from transgenic mice that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1)
GO:0032760 positive regulation of tumor necrosis factor production	IGI PMID:29061364 Inflammatory microglia are glycolytic and iron retentive and...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of tumor necrosis factor production. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (positive regulation of tumor necrosis factor production) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:29061364 retention of iron in microglia increased TNFα expression
GO:0045821 positive regulation of glycolytic process	IGI PMID:29061364 Inflammatory microglia are glycolytic and iron retentive and...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of glycolytic process. Abeta-mediated metabolic effects in cells. Not a core function of APP. Reason: Metabolic effects downstream of Abeta. Not core APP function. Keep as non-core. Supporting Evidence: PMID:29061364 increases in tumor necrosis factor-α (TNFα) and nitric oxide synthase 2 (NOS2) were accompanied by increased glycolysis
GO:0070555 response to interleukin-1	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0005515 protein binding	IPI PMID:28720718 Phosphorylation of amyloid precursor protein by mutant LRRK2...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:28720718 Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson's disease.
GO:1900272 negative regulation of long-term synaptic potentiation	IGI PMID:16636059 Neprilysin-sensitive synapse-associated amyloid-beta peptide...	ACCEPT	Summary: IGI annotation based on genetic interaction evidence. NOTE: Many IGI annotations for APP involve Abeta-specific effects from transgenic mouse studies and may not represent full-length APP function. Reason: IGI annotation supported by genetic interaction data. Note potential cleavage product specificity. Supporting Evidence: PMID:16636059 2006 Apr 24. Neprilysin-sensitive synapse-associated amyloid-beta peptide oligomers impair neuronal plasticity and cognitive function.
GO:0032722 positive regulation of chemokine production	IGI PMID:22406537 A multimodal RAGE-specific inhibitor reduces amyloid β-media...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of chemokine production. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (positive regulation of chemokine production) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:22406537 In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response
GO:0032731 positive regulation of interleukin-1 beta production	IGI PMID:22406537 A multimodal RAGE-specific inhibitor reduces amyloid β-media...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of interleukin-1 beta production. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (positive regulation of interleukin-1 beta production) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:22406537 Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD
GO:0032755 positive regulation of interleukin-6 production	IGI PMID:22406537 A multimodal RAGE-specific inhibitor reduces amyloid β-media...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of interleukin-6 production. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (positive regulation of interleukin-6 production) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:22406537 Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD
GO:0032760 positive regulation of tumor necrosis factor production	IGI PMID:22406537 A multimodal RAGE-specific inhibitor reduces amyloid β-media...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of tumor necrosis factor production. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (positive regulation of tumor necrosis factor production) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:22406537 Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD
GO:0032760 positive regulation of tumor necrosis factor production	IGI PMID:12808450 RAGE mediates amyloid-beta peptide transport across the bloo...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of tumor necrosis factor production. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (positive regulation of tumor necrosis factor production) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:12808450 RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain.
GO:1903523 negative regulation of blood circulation	IGI PMID:12808450 RAGE mediates amyloid-beta peptide transport across the bloo...	KEEP AS NON CORE	Summary: IGI annotation for negative regulation of blood circulation. Vascular effects of Abeta peptides including vasoconstriction and endothelin production. These are pathological consequences of Abeta accumulation rather than core APP functions. Reason: Vascular annotation (negative regulation of blood circulation) is a downstream Abeta-mediated pathological effect. Keep as non-core. Supporting Evidence: PMID:12808450 RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain.
GO:1904472 positive regulation of endothelin production	IGI PMID:12808450 RAGE mediates amyloid-beta peptide transport across the bloo...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of endothelin production. Vascular effects of Abeta peptides including vasoconstriction and endothelin production. These are pathological consequences of Abeta accumulation rather than core APP functions. Reason: Vascular annotation (positive regulation of endothelin production) is a downstream Abeta-mediated pathological effect. Keep as non-core. Supporting Evidence: PMID:12808450 RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain.
GO:0050786 RAGE receptor binding	IPI P05067-PRO_0000000093 PMID:22406537 A multimodal RAGE-specific inhibitor reduces amyloid β-media...	ACCEPT	Summary: IPI annotation for Abeta-RAGE binding. Deane et al. (2012) showed a RAGE inhibitor (FPS-ZM1) blocks Abeta binding to the V domain of RAGE, preventing Abeta-induced cellular stress. This is a core molecular interaction of Abeta. Reason: Well-documented Abeta-RAGE interaction. Annotation correctly applies to Abeta cleavage product. RAGE binding is key to Abeta neurotoxicity mechanism. Supporting Evidence: PMID:22406537 we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Abeta binding to the V domain of RAGE
GO:1901224 positive regulation of non-canonical NF-kappaB signal transduction	IDA PMID:22406537 A multimodal RAGE-specific inhibitor reduces amyloid β-media...	KEEP AS NON CORE	Summary: IDA annotation for positive regulation of non-canonical NF-kappaB signal transduction. Abeta-mediated inflammatory signaling. Downstream effect. Reason: NF-kappaB activation is a downstream inflammatory effect of Abeta. Keep as non-core. Supporting Evidence: PMID:22406537 Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD
GO:0005798 Golgi-associated vesicle	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0055037 recycling endosome	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0005739 mitochondrion	IDA PMID:23525105 Transcriptional regulation of insulin-degrading enzyme modul...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:23525105 2013 Mar 22. Transcriptional regulation of insulin-degrading enzyme modulates mitochondrial amyloid β (Aβ) peptide catabolism and functionality.
GO:0005769 early endosome	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0050890 cognition	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for cognition. Downstream behavioral phenotype of APP/Abeta biology. Not a core molecular function. Reason: Cognition is a high-level phenotype downstream of APP biology. Keep as non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-9617595	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0051087 protein-folding chaperone binding	IPI PMID:23106396 Amyloid-β oligomers are sequestered by both intracellular an...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:23106396 Amyloid-β oligomers are sequestered by both intracellular and extracellular chaperones.
GO:0106003 amyloid-beta complex	IPI PMID:22179788 The extracellular chaperone clusterin sequesters oligomeric ...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:22179788 The extracellular chaperone clusterin sequesters oligomeric forms of the amyloid-β(1-40) peptide.
GO:0031904 endosome lumen	TAS PMID:24305806 Pharmacologic inhibition of ROCK2 suppresses amyloid-β produ...	ACCEPT	Summary: TAS annotation based on author statement in referenced publication. Reason: TAS annotation supported by literature. Supporting Evidence: PMID:24305806 Pharmacologic inhibition of ROCK2 suppresses amyloid-β production in an Alzheimer's disease mouse model.
GO:0010628 positive regulation of gene expression	IGI PMID:27853422 ROCK1 Is Associated with Alzheimer's Disease-Specific Plaque...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: positive regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:27853422 eCollection 2016. ROCK1 Is Associated with Alzheimer's Disease-Specific Plaques, as well as Enhances Autophagosome Formation But not Autophagic Aβ Clearance.
GO:0010628 positive regulation of gene expression	IMP PMID:27853422 ROCK1 Is Associated with Alzheimer's Disease-Specific Plaque...	KEEP AS NON CORE	Summary: IMP annotation for positive regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: positive regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:27853422 eCollection 2016. ROCK1 Is Associated with Alzheimer's Disease-Specific Plaques, as well as Enhances Autophagosome Formation But not Autophagic Aβ Clearance.
GO:0010629 negative regulation of gene expression	IGI PMID:27853422 ROCK1 Is Associated with Alzheimer's Disease-Specific Plaque...	KEEP AS NON CORE	Summary: IGI annotation for negative regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: negative regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:27853422 eCollection 2016. ROCK1 Is Associated with Alzheimer's Disease-Specific Plaques, as well as Enhances Autophagosome Formation But not Autophagic Aβ Clearance.
GO:0007611 learning or memory	IMP PMID:15457210 RAGE potentiates Abeta-induced perturbation of neuronal func...	KEEP AS NON CORE	Summary: IMP annotation for learning or memory. APP and its cleavage products (especially Abeta oligomers) affect learning and memory, but this is a downstream phenotypic consequence of APP processing rather than a core molecular function. Reason: learning or memory is a downstream consequence of APP/Abeta biology. Important for disease relevance but not a core function. Keep as non-core. Supporting Evidence: PMID:15457210 Double Tgs (mutant APP (mAPP)/RAGE) displayed early abnormalities in spatial learning/memory, accompanied by altered activation of markers of synaptic plasticity and exaggerated neuropathologic findings, before such changes were found in mAPP mice
GO:0007611 learning or memory	IGI PMID:15457210 RAGE potentiates Abeta-induced perturbation of neuronal func...	KEEP AS NON CORE	Summary: IGI annotation for learning or memory. APP and its cleavage products (especially Abeta oligomers) affect learning and memory, but this is a downstream phenotypic consequence of APP processing rather than a core molecular function. Reason: learning or memory is a downstream consequence of APP/Abeta biology. Important for disease relevance but not a core function. Keep as non-core. Supporting Evidence: PMID:15457210 Tg mice bearing a dominant-negative RAGE construct targeted to neurons crossed with mAPP animals displayed preservation of spatial learning/memory
GO:0009986 cell surface	NAS PMID:15457210 RAGE potentiates Abeta-induced perturbation of neuronal func...	ACCEPT	Summary: RAGE functions as a cell surface receptor for Abeta. Reason: Paper describes RAGE as signal-transducing cell surface acceptor for Abeta. Supporting Evidence: PMID:15457210 Receptor for Advanced Glycation Endproducts (RAGE), a multiligand receptor in the immunoglobulin superfamily, functions as a signal-transducing cell surface acceptor for amyloid-beta peptide (Abeta)
GO:0070374 positive regulation of ERK1 and ERK2 cascade	IGI PMID:15457210 RAGE potentiates Abeta-induced perturbation of neuronal func...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of ERK1 and ERK2 cascade. Abeta activates MAPK/ERK signaling in various cell types. Downstream signaling effect, not core APP function. Reason: ERK cascade activation is a downstream effect of Abeta. Keep as non-core. Supporting Evidence: PMID:15457210 Receptor for Advanced Glycation Endproducts (RAGE), a multiligand receptor in the immunoglobulin superfamily, functions as a signal-transducing cell surface acceptor for amyloid-beta peptide (Abeta)
GO:1990535 neuron projection maintenance	IGI PMID:20445063 Memory impairment in transgenic Alzheimer mice requires cell...	ACCEPT	Summary: IGI annotation based on genetic interaction evidence. NOTE: Many IGI annotations for APP involve Abeta-specific effects from transgenic mouse studies and may not represent full-length APP function. Reason: IGI annotation supported by genetic interaction data. Note potential cleavage product specificity. Supporting Evidence: PMID:20445063 Memory impairment in transgenic Alzheimer mice requires cellular prion protein.
GO:0007611 learning or memory	IGI PMID:24052308 Human LilrB2 is a β-amyloid receptor and its murine homolog ...	KEEP AS NON CORE	Summary: IGI annotation for learning or memory. APP and its cleavage products (especially Abeta oligomers) affect learning and memory, but this is a downstream phenotypic consequence of APP processing rather than a core molecular function. Reason: learning or memory is a downstream consequence of APP/Abeta biology. Important for disease relevance but not a core function. Keep as non-core. Supporting Evidence: PMID:24052308 Human LilrB2 is a β-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model.
GO:0005178 integrin binding	IDA PMID:21126803 Perlecan domain V inhibits α2 integrin-mediated amyloid-β ne...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:21126803 Perlecan domain V inhibits α2 integrin-mediated amyloid-β neurotoxicity.
GO:0005615 extracellular space	IMP PMID:23640054 Brain interstitial oligomeric amyloid β increases with age a...	ACCEPT	Summary: IMP annotation based on mutant phenotype analysis. Reason: IMP annotation supported by mutant phenotype data. Supporting Evidence: PMID:23640054 Brain interstitial oligomeric amyloid β increases with age and is resistant to clearance from brain in a mouse model of Alzheimer's disease.
GO:0106003 amyloid-beta complex	IMP PMID:23640054 Brain interstitial oligomeric amyloid β increases with age a...	ACCEPT	Summary: IMP annotation based on mutant phenotype analysis. Reason: IMP annotation supported by mutant phenotype data. Supporting Evidence: PMID:23640054 Brain interstitial oligomeric amyloid β increases with age and is resistant to clearance from brain in a mouse model of Alzheimer's disease.
GO:0050750 low-density lipoprotein particle receptor binding	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0030425 dendrite	IDA NOT PMID:17251419 Abeta oligomer-induced aberrations in synapse composition, s...	ACCEPT	Summary: NOT annotation - Lacor et al. (2007) showed Abeta oligomers (ADDLs) bind to dendritic spines, not dendrite shafts. The annotation indicates where full-length APP or its products are NOT found. This study focused on Abeta oligomer binding specificity to excitatory pyramidal neurons. Reason: The negated annotation accurately captures the spatial specificity of Abeta/ADDL binding shown in PMID:17251419. Supporting Evidence: PMID:17251419 ADDLs bound to neurons with specificity, attaching to presumed excitatory pyramidal neurons but not GABAergic neurons... consistent with observed attachment of ADDLs to dendritic spines.
GO:0032590 dendrite membrane	TAS NOT PMID:20032460 Inhibition of calcineurin-mediated endocytosis and alpha-ami...	ACCEPT	Summary: NOT annotation - Zhao et al. (2010) showed that Abeta oligomers (ADDLs) bind specifically to dendritic spines expressing surface AMPA receptors (particularly GluR2), not the general dendrite membrane. The specificity is for postsynaptic compartments. Reason: The negated annotation accurately reflects the spatial selectivity of ADDL binding shown in PMID:20032460. Supporting Evidence: PMID:20032460 ADDL binding occurs in dendritic spines that express surface AMPA receptors, particularly the calcium-impermeable type II AMPA receptor subunit (GluR2).
GO:0005576 extracellular region	TAS Reactome:R-HSA-9010034	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9010034	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9010091	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0031904 endosome lumen	TAS Reactome:R-HSA-5692495	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0031904 endosome lumen	TAS Reactome:R-HSA-9010096	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005615 extracellular space	IDA PMID:23921129 FcγRIIb mediates amyloid-β neurotoxicity and memory impairme...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:23921129 soluble Aβ oligomers interact with FcγRIIb in vitro and in AD brains
GO:0045944 positive regulation of transcription by RNA polymerase II	IGI PMID:23921129 FcγRIIb mediates amyloid-β neurotoxicity and memory impairme...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of transcription by RNA polymerase II. AICD has been reported to regulate transcription through Fe65/Tip60 complex, but this remains controversial and applies to a cleavage product rather than full-length APP. Reason: Transcriptional regulation by AICD is controversial and represents a cleavage product function. Keep as non-core. Supporting Evidence: PMID:23921129 FcγRIIb is significantly upregulated in the hippocampus of AD brains and neuronal cells exposed to synthetic Aβ
GO:0007611 learning or memory	IGI PMID:21113149 Reversing EphB2 depletion rescues cognitive functions in Alz...	KEEP AS NON CORE	Summary: IGI annotation for learning or memory. APP and its cleavage products (especially Abeta oligomers) affect learning and memory, but this is a downstream phenotypic consequence of APP processing rather than a core molecular function. Reason: learning or memory is a downstream consequence of APP/Abeta biology. Important for disease relevance but not a core function. Keep as non-core. Supporting Evidence: PMID:21113149 Reversing EphB2 depletion rescues cognitive functions in Alzheimer model.
GO:0097645 amylin binding	TAS PMID:22500019 Amyloid β (Aβ) peptide directly activates amylin-3 receptor ...	ACCEPT	Summary: TAS annotation based on author statement in referenced publication. Reason: TAS annotation supported by literature. Supporting Evidence: PMID:22500019 2012 Apr 12. Amyloid β (Aβ) peptide directly activates amylin-3 receptor subtype by triggering multiple intracellular signaling pathways.
GO:0010628 positive regulation of gene expression	IGI PMID:22198949 TLR2 is a primary receptor for Alzheimer's amyloid β peptide...	KEEP AS NON CORE	Summary: IGI annotation for positive regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: positive regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:22198949 TLR2-mediated Aβ42-triggered inflammatory activation
GO:0010629 negative regulation of gene expression	IGI PMID:22198949 TLR2 is a primary receptor for Alzheimer's amyloid β peptide...	KEEP AS NON CORE	Summary: IGI annotation for negative regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: negative regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:22198949 TLR2 deficiency in microglia shifts M1- to M2-inflammatory activation in vivo
GO:0005769 early endosome	IDA PMID:26005850 Central role for PICALM in amyloid-β blood-brain barrier tra...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:26005850 guided Aβ trafficking to Rab5 and Rab11
GO:0070381 endosome to plasma membrane transport vesicle	IDA PMID:26005850 Central role for PICALM in amyloid-β blood-brain barrier tra...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:26005850 leading to Aβ endothelial transcytosis and clearance
GO:0005615 extracellular space	IDA PMID:26005850 Central role for PICALM in amyloid-β blood-brain barrier tra...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:26005850 Aβ clearance across the murine blood-brain barrier (BBB)
GO:0048143 astrocyte activation	IGI PMID:20445063 Memory impairment in transgenic Alzheimer mice requires cell...	KEEP AS NON CORE	Summary: IGI annotation for astrocyte activation. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (astrocyte activation) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:20445063 Memory impairment in transgenic Alzheimer mice requires cellular prion protein.
GO:0005109 frizzled binding	IPI PMID:18234671 Amyloid-beta binds to the extracellular cysteine-rich domain...	ACCEPT	Summary: Abeta binds to the Frizzled cysteine-rich domain at or near the Wnt-binding site. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:18234671 Abeta binds to the Fz cysteine-rich domain at or in close proximity to the Wnt-binding site and inhibits the canonical Wnt signaling pathway
GO:0010629 negative regulation of gene expression	IGI PMID:18234671 Amyloid-beta binds to the extracellular cysteine-rich domain...	KEEP AS NON CORE	Summary: IGI annotation for negative regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: negative regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:18234671 Amyloid-beta binds to the extracellular cysteine-rich domain of Frizzled and inhibits Wnt/beta-catenin signaling
GO:0090090 negative regulation of canonical Wnt signaling pathway	IDA PMID:18234671 Amyloid-beta binds to the extracellular cysteine-rich domain...	KEEP AS NON CORE	Summary: IDA annotation for negative regulation of canonical Wnt signaling pathway. APP/Abeta interaction with Wnt signaling components. Not core function. Reason: Wnt signaling regulation is not a core function of APP. Keep as non-core. Supporting Evidence: PMID:18234671 Abeta binds to the Fz cysteine-rich domain at or in close proximity to the Wnt-binding site and inhibits the canonical Wnt signaling pathway
GO:1900181 negative regulation of protein localization to nucleus	IGI PMID:18234671 Amyloid-beta binds to the extracellular cysteine-rich domain...	ACCEPT	Summary: By inhibiting Wnt signaling, Abeta prevents beta-catenin nuclear localization required for Wnt target gene activation. Reason: IGI annotation reflects Abeta blocking beta-catenin nuclear translocation by inhibiting Wnt signaling. Supporting Evidence: PMID:18234671 Amyloid-beta binds to the extracellular cysteine-rich domain of Frizzled and inhibits Wnt/beta-catenin signaling
GO:0002265 astrocyte activation involved in immune response	IGI PMID:23152628 LRP1 in brain vascular smooth muscle cells mediates local cl...	KEEP AS NON CORE	Summary: IGI annotation for astrocyte activation involved in immune response. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (astrocyte activation involved in immune response) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:23152628 LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer's amyloid-β.
GO:0005764 lysosome	IDA PMID:23152628 LRP1 in brain vascular smooth muscle cells mediates local cl...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:23152628 LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer's amyloid-β.
GO:0043395 heparan sulfate proteoglycan binding	IMP PMID:21289173 Heparan sulphate proteoglycan and the low-density lipoprotei...	ACCEPT	Summary: IMP annotation based on mutant phenotype analysis. Reason: IMP annotation supported by mutant phenotype data. Supporting Evidence: PMID:21289173 Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-beta uptake.
GO:1904399 heparan sulfate binding	TAS PMID:21289173 Heparan sulphate proteoglycan and the low-density lipoprotei...	ACCEPT	Summary: TAS annotation based on author statement in referenced publication. Reason: TAS annotation supported by literature. Supporting Evidence: PMID:21289173 Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-beta uptake.
GO:1904646 cellular response to amyloid-beta	IGI PMID:23152628 LRP1 in brain vascular smooth muscle cells mediates local cl...	ACCEPT	Summary: IGI annotation based on genetic interaction evidence. NOTE: Many IGI annotations for APP involve Abeta-specific effects from transgenic mouse studies and may not represent full-length APP function. Reason: IGI annotation supported by genetic interaction data. Note potential cleavage product specificity. Supporting Evidence: PMID:23152628 LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer's amyloid-β.
GO:0032991 protein-containing complex	IDA PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex with low density lipoprotein receptor-related protein-2/megalin.
GO:0034185 apolipoprotein binding	IPI PMID:22138302 Preferential interactions between ApoE-containing lipoprotei...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:22138302 Preferential interactions between ApoE-containing lipoproteins and Aβ revealed by a detection method that combines size exclusion chromatography with non-reducing gel-shift.
GO:0034363 intermediate-density lipoprotein particle	IDA PMID:22138302 Preferential interactions between ApoE-containing lipoprotei...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:22138302 Preferential interactions between ApoE-containing lipoproteins and Aβ revealed by a detection method that combines size exclusion chromatography with non-reducing gel-shift.
GO:0034364 high-density lipoprotein particle	IDA PMID:22138302 Preferential interactions between ApoE-containing lipoprotei...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:22138302 Preferential interactions between ApoE-containing lipoproteins and Aβ revealed by a detection method that combines size exclusion chromatography with non-reducing gel-shift.
GO:0051087 protein-folding chaperone binding	IPI PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex with low density lipoprotein receptor-related protein-2/megalin.
GO:1990777 lipoprotein particle	IDA PMID:22138302 Preferential interactions between ApoE-containing lipoprotei...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:22138302 Preferential interactions between ApoE-containing lipoproteins and Aβ revealed by a detection method that combines size exclusion chromatography with non-reducing gel-shift.
GO:0010628 positive regulation of gene expression	IMP PMID:23164821 Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven...	KEEP AS NON CORE	Summary: IMP annotation for positive regulation of gene expression. Gene expression changes are downstream effects of APP processing and Abeta signaling. Some may be mediated by AICD transcriptional regulation (controversial). Not core APP function. Reason: positive regulation of gene expression is a downstream effect. Keep as non-core. Supporting Evidence: PMID:23164821 Aβ induction of DKK1 and all five of the common genes, including EGR1, NAB2 and KLF10, was significantly blocked by the silencing of CLU
GO:0008285 negative regulation of cell population proliferation	IDA PMID:22944668 Antimicrobial activity of human islet amyloid polypeptides: ...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:22944668 Antimicrobial activity of human islet amyloid polypeptides: an insight into amyloid peptides' connection with antimicrobial peptides.
GO:0034185 apolipoprotein binding	IPI PMID:9211985 Association of human, rat, and rabbit apolipoprotein E with ...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:9211985 These binding studies provide one possible explanation for protective effects of both apoE2 and E3 against the development of Alzheimer's disease
GO:0042157 lipoprotein metabolic process	IC PMID:9211985 Association of human, rat, and rabbit apolipoprotein E with ...	ACCEPT	Summary: IC annotation inferred by curator based on available evidence. Reason: IC annotation supported by curator judgment. Supporting Evidence: PMID:9211985 In humans, apolipoprotein E (apoE) has three major isoforms
GO:0098815 modulation of excitatory postsynaptic potential	IGI PMID:20974225 Activation of nicotinic α(7) acetylcholine receptor enhances...	ACCEPT	Summary: IGI annotation based on genetic interaction evidence. NOTE: Many IGI annotations for APP involve Abeta-specific effects from transgenic mouse studies and may not represent full-length APP function. Reason: IGI annotation supported by genetic interaction data. Note potential cleavage product specificity. Supporting Evidence: PMID:20974225 Epub 2010 Oct 23. Activation of nicotinic α(7) acetylcholine receptor enhances long term potentation in wild type mice but not in APP(swe)/PS1ΔE9 mice.
GO:1900273 positive regulation of long-term synaptic potentiation	IGI PMID:20974225 Activation of nicotinic α(7) acetylcholine receptor enhances...	ACCEPT	Summary: IGI annotation based on genetic interaction evidence. NOTE: Many IGI annotations for APP involve Abeta-specific effects from transgenic mouse studies and may not represent full-length APP function. Reason: IGI annotation supported by genetic interaction data. Note potential cleavage product specificity. Supporting Evidence: PMID:20974225 Epub 2010 Oct 23. Activation of nicotinic α(7) acetylcholine receptor enhances long term potentation in wild type mice but not in APP(swe)/PS1ΔE9 mice.
GO:0097060 synaptic membrane	IDA NOT PMID:17308309 Abeta oligomers induce neuronal oxidative stress through an ...	ACCEPT	Summary: NOT annotation - De Felice et al. (2007) showed Abeta oligomers (ADDLs) bind specifically at or near NMDA receptors, not the general synaptic membrane. The study showed ADDLs co-immunoprecipitate with NMDA-R subunits and require NMDA-R activation for their effects. Reason: The negated annotation accurately captures the receptor-specific binding of ADDLs shown in PMID:17308309, distinguishing binding specificity from general synaptic membrane localization. Supporting Evidence: PMID:17308309 ADDLs that were bound to detergent-extracted synaptosomal membranes co-immunoprecipitated with NMDA-R subunits... ADDLs bind to or in close proximity to NMDA-Rs, triggering neuronal damage through NMDA-R-dependent calcium flux.
GO:0032991 protein-containing complex	IPI P05067-PRO_0000000093 PMID:18568035 Amyloid-beta protein dimers isolated directly from Alzheimer...	ACCEPT	Summary: IPI annotation for Abeta complex formation. Shankar et al. (2008) showed that Abeta dimers (Abeta42-Abeta40 complexes) are the minimal synaptotoxic species. The IPI annotation correctly captures that Abeta42 forms complexes with Abeta40. Reason: Well-supported IPI annotation correctly targeting Abeta cleavage product. Dimerization is essential for synaptotoxicity. Supporting Evidence: PMID:18568035 These various effects were specifically attributable to Abeta dimers
GO:0061844 antimicrobial humoral immune response mediated by antimicrobial peptide	IMP PMID:20209079 The Alzheimer's disease-associated amyloid beta-protein is a...	KEEP AS NON CORE	Summary: IMP annotation for antimicrobial humoral immune response mediated by antimicrobial peptide. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (antimicrobial humoral immune response mediated by antimicrobial peptide) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:20209079 Abeta exerts antimicrobial activity against eight common and clinically relevant microorganisms with a potency equivalent to, and in some cases greater than, LL-37
GO:0046982 protein heterodimerization activity	IPI P05067-PRO_0000000093 PMID:18568035 Amyloid-beta protein dimers isolated directly from Alzheimer...	ACCEPT	Summary: IPI annotation for Abeta heterodimerization. GOA shows Abeta42 (PRO_0000000093) heterodimerizes with Abeta40 (PRO_0000000092). Shankar et al. (2008) demonstrated that Abeta dimers are the smallest synaptotoxic species. Reason: Well-supported IPI annotation correctly targeting Abeta42. The Abeta42-Abeta40 heterodimer is the pathogenic species. Supporting Evidence: PMID:18568035 These various effects were specifically attributable to Abeta dimers
GO:0051247 positive regulation of protein metabolic process	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0005886 plasma membrane	IDA PMID:20164328 Loss of alpha7 nicotinic receptors enhances beta-amyloid oli...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:20164328 Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease.
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-8952289	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0007611 learning or memory	IGI PMID:19587288 Deletion of the alpha 7 nicotinic acetylcholine receptor gen...	KEEP AS NON CORE	Summary: IGI annotation for learning or memory. APP and its cleavage products (especially Abeta oligomers) affect learning and memory, but this is a downstream phenotypic consequence of APP processing rather than a core molecular function. Reason: learning or memory is a downstream consequence of APP/Abeta biology. Important for disease relevance but not a core function. Keep as non-core. Supporting Evidence: PMID:19587288 Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease.
GO:0050808 synapse organization	IGI PMID:19587288 Deletion of the alpha 7 nicotinic acetylcholine receptor gen...	ACCEPT	Summary: IGI annotation based on genetic interaction evidence. NOTE: Many IGI annotations for APP involve Abeta-specific effects from transgenic mouse studies and may not represent full-length APP function. Reason: IGI annotation supported by genetic interaction data. Note potential cleavage product specificity. Supporting Evidence: PMID:19587288 Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease.
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-8871506	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:1990000 amyloid fibril formation	IMP PMID:25620700 A genome-wide gene-expression analysis and database in trans...	ACCEPT	Summary: IMP annotation based on mutant phenotype analysis. Reason: IMP annotation supported by mutant phenotype data. Supporting Evidence: PMID:25620700 2015 Jan 22. A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology.
GO:0001878 response to yeast	IMP PMID:20209079 The Alzheimer's disease-associated amyloid beta-protein is a...	KEEP AS NON CORE	Summary: IMP annotation for response to yeast. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (response to yeast) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:20209079 anti-Abeta immunoreactive material in AD whole brain homogenates is active against Candida albicans, the pathogen we identified as most sensitive to synthetic Abeta
GO:0019731 antibacterial humoral response	IDA PMID:20209079 The Alzheimer's disease-associated amyloid beta-protein is a...	KEEP AS NON CORE	Summary: IDA annotation for antibacterial humoral response. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (antibacterial humoral response) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:20209079 Abeta exerts antimicrobial activity against eight common and clinically relevant microorganisms with a potency equivalent to, and in some cases greater than, LL-37
GO:0019732 antifungal humoral response	IMP PMID:20209079 The Alzheimer's disease-associated amyloid beta-protein is a...	KEEP AS NON CORE	Summary: IMP annotation for antifungal humoral response. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (antifungal humoral response) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:20209079 anti-Abeta immunoreactive material in AD whole brain homogenates is active against Candida albicans, the pathogen we identified as most sensitive to synthetic Abeta
GO:0045087 innate immune response	IMP PMID:20209079 The Alzheimer's disease-associated amyloid beta-protein is a...	KEEP AS NON CORE	Summary: IMP annotation for innate immune response. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (innate immune response) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:20209079 Our findings suggest Abeta is a hitherto unrecognized AMP that may normally function in the innate immune system
GO:0050829 defense response to Gram-negative bacterium	IDA PMID:20209079 The Alzheimer's disease-associated amyloid beta-protein is a...	KEEP AS NON CORE	Summary: IDA annotation for defense response to Gram-negative bacterium. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (defense response to Gram-negative bacterium) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:20209079 The synthetic Abeta peptides demonstrated antibiotic activity against Gram-negative and Gram-positive bacteria and the yeast C. albicans
GO:0050830 defense response to Gram-positive bacterium	IDA PMID:20209079 The Alzheimer's disease-associated amyloid beta-protein is a...	KEEP AS NON CORE	Summary: IDA annotation for defense response to Gram-positive bacterium. These immune/inflammatory effects are primarily mediated by Abeta cleavage products activating innate immune cells (microglia, astrocytes) rather than representing core functions of full-length APP. Reason: Immune/inflammatory annotation (defense response to Gram-positive bacterium) reflects downstream Abeta-mediated effects. Not a core function of APP itself. Keep as non-core. Supporting Evidence: PMID:20209079 The synthetic Abeta peptides demonstrated antibiotic activity against Gram-negative and Gram-positive bacteria and the yeast C. albicans
GO:0031904 endosome lumen	TAS Reactome:R-HSA-6783332	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005515 protein binding	IPI PMID:11238726 Fibulin-1 binds the amino-terminal head of beta-amyloid prec...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:11238726 Fibulin-1 binds the amino-terminal head of beta-amyloid precursor protein and modulates its physiological function.
GO:0005768 endosome	IDA PMID:18353773 A novel sorting nexin modulates endocytic trafficking and al...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:18353773 2008 Mar 19. A novel sorting nexin modulates endocytic trafficking and alpha-secretase cleavage of the amyloid precursor protein.
GO:0009986 cell surface	IDA PMID:18353773 A novel sorting nexin modulates endocytic trafficking and al...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:18353773 2008 Mar 19. A novel sorting nexin modulates endocytic trafficking and alpha-secretase cleavage of the amyloid precursor protein.
GO:0005515 protein binding	IPI PMID:24336208 Rare coding variants in the phospholipase D3 gene confer ris...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:24336208 Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease.
GO:0005615 extracellular space	HDA PMID:16502470 Human colostrum: identification of minor proteins in the aqu...	ACCEPT	Summary: HDA annotation from high-throughput direct assay. Reason: HDA annotation supported by experimental data. Supporting Evidence: PMID:16502470 Human colostrum: identification of minor proteins in the aqueous phase by proteomics.
GO:0019899 enzyme binding	IPI PMID:24499793 FKBP12 regulates the localization and processing of amyloid ...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:24499793 FKBP12 regulates the localization and processing of amyloid precursor protein in human cell lines.
GO:0045121 membrane raft	IDA PMID:24499793 FKBP12 regulates the localization and processing of amyloid ...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:24499793 FKBP12 regulates the localization and processing of amyloid precursor protein in human cell lines.
GO:0005515 protein binding	IPI PMID:16407538 Interaction of the cytosolic domains of sorLA/LR11 with the ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:16407538 Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme.
GO:0005641 nuclear envelope lumen	IDA PMID:21989385 Quantitative modelling of amyloidogenic processing and its i...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:21989385 Quantitative modelling of amyloidogenic processing and its influence by SORLA in Alzheimer's disease.
GO:0043235 receptor complex	IDA PMID:23382219 Structural basis for endosomal trafficking of diverse transm...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:23382219 Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.
GO:0070062 extracellular exosome	HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid...	ACCEPT	Summary: HDA annotation from high-throughput direct assay. Reason: HDA annotation supported by experimental data. Supporting Evidence: PMID:19199708 Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).
GO:0005794 Golgi apparatus	IDA PMID:20427278 The novel membrane protein TMEM59 modulates complex glycosyl...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:20427278 2010 Apr 28. The novel membrane protein TMEM59 modulates complex glycosylation, cell surface expression, and secretion of the amyloid precursor protein.
GO:0005886 plasma membrane	IDA PMID:20427278 The novel membrane protein TMEM59 modulates complex glycosyl...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:20427278 2010 Apr 28. The novel membrane protein TMEM59 modulates complex glycosylation, cell surface expression, and secretion of the amyloid precursor protein.
GO:0048471 perinuclear region of cytoplasm	IDA PMID:20427278 The novel membrane protein TMEM59 modulates complex glycosyl...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:20427278 2010 Apr 28. The novel membrane protein TMEM59 modulates complex glycosylation, cell surface expression, and secretion of the amyloid precursor protein.
GO:0005576 extracellular region	TAS Reactome:R-HSA-481007	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005829 cytosol	TAS Reactome:R-HSA-1296421	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005829 cytosol	TAS Reactome:R-HSA-844440	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005829 cytosol	TAS Reactome:R-HSA-844610	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005829 cytosol	TAS Reactome:R-HSA-844612	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0031093 platelet alpha granule lumen	TAS Reactome:R-HSA-481007	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0031904 endosome lumen	TAS Reactome:R-HSA-5229111	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0031904 endosome lumen	TAS Reactome:R-HSA-8871494	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0031904 endosome lumen	TAS Reactome:R-HSA-8871506	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0031904 endosome lumen	TAS Reactome:R-HSA-9010091	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0032588 trans-Golgi network membrane	TAS Reactome:R-HSA-5229111	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0032588 trans-Golgi network membrane	TAS Reactome:R-HSA-5229132	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2467665	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6783332	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005576 extracellular region	TAS Reactome:R-HSA-879411	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005576 extracellular region	TAS Reactome:R-HSA-976734	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005576 extracellular region	TAS Reactome:R-HSA-977136	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005576 extracellular region	TAS Reactome:R-NUL-997411	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005576 extracellular region	TAS Reactome:R-HSA-379048	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005576 extracellular region	TAS Reactome:R-HSA-380073	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005576 extracellular region	TAS Reactome:R-HSA-391913	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005576 extracellular region	TAS Reactome:R-HSA-749448	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005576 extracellular region	TAS Reactome:R-HSA-749452	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005576 extracellular region	TAS Reactome:R-HSA-749454	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005576 extracellular region	TAS Reactome:R-HSA-749456	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005576 extracellular region	TAS Reactome:R-HSA-8870710	ACCEPT	Summary: TAS annotation from Reactome pathway database. Reason: Reactome annotation consistent with known APP biology and pathway involvement.
GO:0005515 protein binding	IPI PMID:18468999 Regulation of FE65 nuclear translocation and function by amy...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:18468999 2008 May 9. Regulation of FE65 nuclear translocation and function by amyloid beta-protein precursor in osmotically stressed cells.
GO:0005886 plasma membrane	IDA PMID:12805363 Autosomal recessive hypercholesterolemia protein interacts w...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:12805363 2003 Jun 12. Autosomal recessive hypercholesterolemia protein interacts with and regulates the cell surface level of Alzheimer's amyloid beta precursor protein.
GO:0051425 PTB domain binding	IPI PMID:12805363 Autosomal recessive hypercholesterolemia protein interacts w...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:12805363 2003 Jun 12. Autosomal recessive hypercholesterolemia protein interacts with and regulates the cell surface level of Alzheimer's amyloid beta precursor protein.
GO:0005515 protein binding	IPI PMID:18509662 Close association of water channel AQP1 with amyloid-beta de...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:18509662 2008 May 29. Close association of water channel AQP1 with amyloid-beta deposition in Alzheimer disease brains.
GO:0005737 cytoplasm	IDA PMID:18509662 Close association of water channel AQP1 with amyloid-beta de...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:18509662 2008 May 29. Close association of water channel AQP1 with amyloid-beta deposition in Alzheimer disease brains.
GO:0005102 signaling receptor binding	IPI PMID:19849849 CD74 interacts with APP and suppresses the production of Abe...	ACCEPT	Summary: IPI annotation showing specific protein interaction. Reason: IPI annotation with specific molecular function is more informative than generic protein binding. Supporting Evidence: PMID:19849849 CD74 interacts with APP and suppresses the production of Abeta.
GO:0005515 protein binding	IPI PMID:19849849 CD74 interacts with APP and suppresses the production of Abe...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:19849849 CD74 interacts with APP and suppresses the production of Abeta.
GO:0005515 protein binding	IPI PMID:19901339 RAGE-mediated signaling contributes to intraneuronal transpo...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:19901339 RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction.
GO:0043197 dendritic spine	IDA PMID:11988176 The acid-activated ion channel ASIC contributes to synaptic ...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:11988176 The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory.
GO:0043198 dendritic shaft	IDA PMID:11988176 The acid-activated ion channel ASIC contributes to synaptic ...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:11988176 The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory.
GO:0045202 synapse	IDA PMID:11988176 The acid-activated ion channel ASIC contributes to synaptic ...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:11988176 The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory.
GO:0003677 DNA binding	ISS GO_REF:0000024	UNDECIDED	Summary: ISS annotation for DNA binding. The AICD fragment has been reported to associate with transcription factor complexes (Fe65/Tip60) and regulate gene expression, but whether AICD itself directly binds DNA remains controversial. Most evidence suggests AICD acts as a transcriptional co-activator through protein-protein interactions rather than direct DNA binding. Reason: The claim that APP/AICD directly binds DNA is not well-supported. AICD associates with DNA-binding complexes but may not bind DNA directly. This annotation needs further experimental validation.
GO:0005737 cytoplasm	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0005794 Golgi apparatus	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0006417 regulation of translation	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0006878 intracellular copper ion homeostasis	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0006897 endocytosis	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0007409 axonogenesis	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0007617 mating behavior	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for mating behavior based on mouse APP knockout/transgenic studies. These behavioral phenotypes reflect pleiotropic downstream effects of APP loss or Abeta overexpression in mice rather than a core molecular function of APP. Reason: Behavioral phenotype (mating behavior) observed in mouse models. Not a core function of APP but a downstream consequence. Keep as non-core.
GO:0007626 locomotory behavior	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for locomotory behavior based on mouse APP knockout/transgenic studies. These behavioral phenotypes reflect pleiotropic downstream effects of APP loss or Abeta overexpression in mice rather than a core molecular function of APP. Reason: Behavioral phenotype (locomotory behavior) observed in mouse models. Not a core function of APP but a downstream consequence. Keep as non-core.
GO:0008088 axo-dendritic transport	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0008344 adult locomotory behavior	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for adult locomotory behavior based on mouse APP knockout/transgenic studies. These behavioral phenotypes reflect pleiotropic downstream effects of APP loss or Abeta overexpression in mice rather than a core molecular function of APP. Reason: Behavioral phenotype (adult locomotory behavior) observed in mouse models. Not a core function of APP but a downstream consequence. Keep as non-core.
GO:0008542 visual learning	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for visual learning based on mouse APP knockout/transgenic studies. These behavioral phenotypes reflect pleiotropic downstream effects of APP loss or Abeta overexpression in mice rather than a core molecular function of APP. Reason: Behavioral phenotype (visual learning) observed in mouse models. Not a core function of APP but a downstream consequence. Keep as non-core.
GO:0016020 membrane	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0016199 axon midline choice point recognition	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0016322 neuron remodeling	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0016358 dendrite development	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0030198 extracellular matrix organization	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0030424 axon	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0031175 neuron projection development	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0035235 ionotropic glutamate receptor signaling pathway	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0040014 regulation of multicellular organism growth	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0045931 positive regulation of mitotic cell cycle	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for positive regulation of mitotic cell cycle. Some evidence suggests AICD can regulate cell cycle genes, but this is not a core function of APP in neurons (which are post-mitotic). Reason: Cell cycle regulation is not a core function of APP, particularly in neurons which are post-mitotic. Keep as non-core.
GO:0048669 collateral sprouting in absence of injury	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0050803 regulation of synapse structure or activity	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on sequence similarity to characterized ortholog. Reason: ISS annotation consistent with known APP functions.
GO:0005515 protein binding	IPI PMID:18026102 Cystatin C modulates cerebral beta-amyloidosis.	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:18026102 Cystatin C modulates cerebral beta-amyloidosis.
GO:0005515 protein binding	IPI PMID:14557245 APP-BP1 mediates APP-induced apoptosis and DNA synthesis and...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:14557245 APP-BP1 mediates APP-induced apoptosis and DNA synthesis and is increased in Alzheimer's disease brain.
GO:0005515 protein binding	IPI PMID:8626687 APP-BP1, a novel protein that binds to the carboxyl-terminal...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:8626687 APP-BP1, a novel protein that binds to the carboxyl-terminal region of the amyloid precursor protein.
GO:0004867 serine-type endopeptidase inhibitor activity	IDA PMID:10652580 Production of amyloid beta protein precursor as a proteinase...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:10652580 Production of amyloid beta protein precursor as a proteinase inhibitor by human astrocytic tumors.
GO:0009986 cell surface	IDA PMID:7593229 Serine proteinase inhibitors in human skeletal muscle: expre...	ACCEPT	Summary: IDA annotation based on direct experimental assay. Reason: IDA annotation supported by direct experimental evidence. Supporting Evidence: PMID:7593229 Serine proteinase inhibitors in human skeletal muscle: expression of beta-amyloid protein precursor and alpha 1-antichymotrypsin in vivo and during myogenesis in vitro.
GO:0005886 plasma membrane	TAS PMID:10806211 Phosphorylation of the beta-amyloid precursor protein at the...	ACCEPT	Summary: TAS annotation based on author statement in referenced publication. Reason: TAS annotation supported by literature. Supporting Evidence: PMID:10806211 Phosphorylation of the beta-amyloid precursor protein at the cell surface by ectocasein kinases 1 and 2.
GO:0005515 protein binding	IPI PMID:10081969 Molecular cloning of human Fe65L2 and its interaction with t...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:10081969 Molecular cloning of human Fe65L2 and its interaction with the Alzheimer's beta-amyloid precursor protein.
GO:0005515 protein binding	IPI PMID:10049767 X11L2, a new member of the X11 protein family, interacts wit...	MARK AS OVER ANNOTATED	Summary: IPI protein binding annotation. Generic protein binding does not provide specific functional information. Reason: Generic protein binding uninformative - should use more specific MF terms. Supporting Evidence: PMID:10049767 X11L2, a new member of the X11 protein family, interacts with Alzheimer's beta-amyloid precursor protein.

Core Functions

Full-length APP functions as a cell surface adhesion molecule. APP molecules on neighboring cells engage in trans-dimerization to promote synaptogenesis and cell-cell contact. This is a physiological function of full-length APP at the plasma membrane.

Molecular Function:

cell adhesion mediator activity

Directly Involved In:

cell adhesion

Cellular Locations:

plasma membrane cell surface

Supporting Evidence:

file:human/APP/APP-deep-research-falcon.md

APP regulates axon development through multiple mechanisms. The sAPPalpha ectodomain promotes neurite outgrowth acting as a signaling ligand, while full-length APP interacts with Fe65/Mena to guide axon growth. APP knockout mice show defects in axonogenesis.

Molecular Function:

signaling receptor activator activity

Directly Involved In:

axonogenesis neuron projection development

Cellular Locations:

plasma membrane growth cone

Supporting Evidence:

file:human/APP/APP-deep-research-falcon.md

APP is highly expressed at synapses and plays physiological roles in synapse formation, maintenance, and plasticity. APP trans-dimerization across the synaptic cleft mediates cell-cell adhesion that contributes to synapse structure. APP knockout models show synaptic deficits.

Molecular Function:

cell adhesion molecule binding

Directly Involved In:

regulation of synapse structure or activity

Cellular Locations:

plasma membrane neuron projection

Supporting Evidence:

file:human/APP/APP-deep-research-falcon.md

APP binds copper and zinc ions via its ectodomain (GFLD/copper-binding domain) and participates in copper homeostasis and reduction of Cu(2+) to Cu(+). This is a direct molecular function of the APP ectodomain.

Molecular Function:

copper ion binding

Directly Involved In:

intracellular copper ion homeostasis

Cellular Locations:

plasma membrane early endosome

Supporting Evidence:

file:human/APP/APP-deep-research-falcon.md

ISOFORM-SPECIFIC: The Kunitz protease inhibitor (KPI) domain in APP751/770 isoforms confers serine protease inhibitor activity (Protease nexin-II function). Absent from the neuronal APP695 isoform.

Molecular Function:

serine-type endopeptidase inhibitor activity

Cellular Locations:

extracellular region plasma membrane

Supporting Evidence:

file:human/APP/APP-deep-research-falcon.md

CLEAVAGE PRODUCT FUNCTION: Abeta peptides (particularly Abeta42) self-assemble into amyloid fibrils via identical protein binding. This is a defining biochemical property of the Abeta cleavage products of APP and is central to Alzheimer disease pathology. Both full-length APP and Abeta cleavage products engage in homodimerization.

Molecular Function:

identical protein binding

Directly Involved In:

amyloid fibril formation

Cellular Locations:

extracellular region early endosome

Supporting Evidence:

file:human/APP/APP-deep-research-falcon.md

APP ectodomain binds heparin and heparan sulfate proteoglycans. This interaction promotes APP dimerization, influences neurite outgrowth, and modulates cell adhesion functions.

Molecular Function:

heparin binding

Directly Involved In:

cell adhesion

Cellular Locations:

plasma membrane cell surface

Supporting Evidence:

file:human/APP/APP-deep-research-falcon.md

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000114

Manual transfer of experimentally-verified manual GO annotation data to homologous complexes by curator judgment of sequence, composition and function similarity

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10049767

X11L2, a new member of the X11 protein family, interacts with Alzheimer's beta-amyloid precursor protein.

PMID:10081969

Molecular cloning of human Fe65L2 and its interaction with the Alzheimer's beta-amyloid precursor protein.

PMID:10652580

Production of amyloid beta protein precursor as a proteinase inhibitor by human astrocytic tumors.

PMID:10673326

Agrin binds to beta-amyloid (Abeta), accelerates abeta fibril formation, and is localized to Abeta deposits in Alzheimer's disease brain.

PMID:10677483

Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein.

PMID:10681545

beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology.

PMID:10806211

Phosphorylation of the beta-amyloid precursor protein at the cell surface by ectocasein kinases 1 and 2.

PMID:11140684

A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease.

PMID:11238726

Fibulin-1 binds the amino-terminal head of beta-amyloid precursor protein and modulates its physiological function.

PMID:11278849

beta -Amyloid peptide-induced apoptosis regulated by a novel protein containing a g protein activation module.

PMID:11297421

Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits A beta aggregation and toxicity.

PMID:11404397

Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer's disease.

PMID:11724784

Jun NH2-terminal kinase (JNK) interacting protein 1 (JIP1) binds the cytoplasmic domain of the Alzheimer's beta-amyloid precursor protein (APP).

PMID:11756426

Amyloid beta binds trimers as well as monomers of the 75-kDa neurotrophin receptor and activates receptor signaling.

PMID:11877420

Tyrosine phosphorylation of the beta-amyloid precursor protein cytoplasmic tail promotes interaction with Shc.

PMID:11880515

The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease.

PMID:11988176

The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory.

PMID:12054541

A secreted form of human ADAM9 has an alpha-secretase activity for APP.

PMID:12485888

Signal transduction through tyrosine-phosphorylated carboxy-terminal fragments of APP via an enhanced interaction with Shc/Grb2 adaptor proteins in reactive astrocytes of Alzheimer's disease brain.

PMID:12805363

Autosomal recessive hypercholesterolemia protein interacts with and regulates the cell surface level of Alzheimer's amyloid beta precursor protein.

PMID:12808450

RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain.

PMID:12901838

Presenilin-1 interacts directly with the beta-site amyloid protein precursor cleaving enzyme (BACE1).

PMID:14527950

Generation of the beta-amyloid peptide and the amyloid precursor protein C-terminal fragment gamma are potentiated by FE65L1.

PMID:14557245

APP-BP1 mediates APP-induced apoptosis and DNA synthesis and is increased in Alzheimer's disease brain.

PMID:15447668

MAPK recruitment by beta-amyloid in organotypic hippocampal slice cultures depends on physical state and exposure time.

PMID:15457210

RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice.

PMID:15615705

CLAC binds to amyloid beta peptides through the positively charged amino acid cluster within the collagenous domain 1 and inhibits formation of amyloid fibrils.

PMID:15896298

In cerebrospinal fluid ER chaperones ERp57 and calreticulin bind beta-amyloid.

PMID:16027166

BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid beta (Abeta) production.

PMID:16049941

A pilot proteomic study of amyloid precursor interactors in Alzheimer's disease.

PMID:16174740

Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein.

PMID:16286452

Gerstmann-Sträussler-Scheinker disease amyloid protein polymerizes according to the "dock-and-lock" model.

PMID:16374483

Neurofibromatosis type 1 protein and amyloid precursor protein interact in normal human melanocytes and colocalize with melanosomes.

PMID:16407538

Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme.

PMID:16446437

Abeta and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer's disease.

PMID:16480949

The intracellular domain of amyloid precursor protein interacts with flotillin-1, a lipid raft protein.

PMID:16502470

Human colostrum: identification of minor proteins in the aqueous phase by proteomics.

PMID:16554819

The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production.

PMID:16636059

Neprilysin-sensitive synapse-associated amyloid-beta peptide oligomers impair neuronal plasticity and cognitive function.

PMID:17051221

Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism.

PMID:17112471

ADAM19 is tightly associated with constitutive Alzheimer's disease APP alpha-secretase in A172 cells.

PMID:17112520

Aluminum inhibits proteolytic degradation of amyloid beta peptide by cathepsin D: a potential link between aluminum accumulation and neuritic plaque deposition.

PMID:17116874

Blocking the apolipoprotein E/amyloid-beta interaction as a potential therapeutic approach for Alzheimer's disease.

PMID:17251419

Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease.

PMID:17255335

Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice.

PMID:17308309

Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine.

PMID:17360908

Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway.

PMID:17709753

Amyolid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter.

PMID:18026102

Cystatin C modulates cerebral beta-amyloidosis.

PMID:18059284

Evidence of fibril-like β-sheet structures in a neurotoxic amyloid intermediate of Alzheimer's β-amyloid.

PMID:18234671

Amyloid-beta binds to the extracellular cysteine-rich domain of Frizzled and inhibits Wnt/beta-catenin signaling.

PMID:18353773

A novel sorting nexin modulates endocytic trafficking and alpha-secretase cleavage of the amyloid precursor protein.

PMID:18468999

Regulation of FE65 nuclear translocation and function by amyloid beta-protein precursor in osmotically stressed cells.

PMID:18483195

Paired beta-sheet structure of an Abeta(1-40) amyloid fibril revealed by electron microscopy.

PMID:18499799

Two-dimensional infrared spectra of isotopically diluted amyloid fibrils from Abeta40.

PMID:18509662

Close association of water channel AQP1 with amyloid-beta deposition in Alzheimer disease brains.

PMID:18568035

Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.

PMID:18602473

Aggregation and catabolism of disease-associated intra-Abeta mutations: reduced proteolysis of AbetaA21G by neprilysin.

PMID:18805418

In vitro perturbation of aggregation processes in beta-amyloid peptides: a spectroscopic study.

PMID:18806802

Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease.

PMID:19199708

Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).

PMID:19242475

Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers.

PMID:19304802

Synaptic transmission block by presynaptic injection of oligomeric amyloid beta.

PMID:19458258

Alpha-helix targeting reduces amyloid-beta peptide toxicity.

PMID:19549187

Quenched hydrogen/deuterium exchange NMR characterization of amyloid-beta peptide aggregates formed in the presence of Cu2+ or Zn2+.

PMID:19587288

Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease.

PMID:19660551

Biochemical and immunohistochemical analysis of an Alzheimer's disease mouse model reveals the presence of multiple cerebral Abeta assembly forms throughout life.

PMID:19706468

Structure-neurotoxicity relationships of amyloid beta-protein oligomers.

PMID:19706519

Measurement of amyloid fibril mass-per-length by tilted-beam transmission electron microscopy.

PMID:19726636

Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis.

PMID:19754881

The thioflavin T fluorescence assay for amyloid fibril detection can be biased by the presence of exogenous compounds.

PMID:19841277

Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity.

PMID:19849849

CD74 interacts with APP and suppresses the production of Abeta.

PMID:19901339

RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction.

PMID:20032460

Inhibition of calcineurin-mediated endocytosis and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors prevents amyloid beta oligomer-induced synaptic disruption.

PMID:20133839

Mechanism of amyloid plaque formation suggests an intracellular basis of Abeta pathogenicity.

PMID:20164328

Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease.

PMID:20195357

A comprehensive resource of interacting protein regions for refining human transcription factor networks.

PMID:20209079

The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide.

PMID:20427278

The novel membrane protein TMEM59 modulates complex glycosylation, cell surface expression, and secretion of the amyloid precursor protein.

PMID:20445063

Memory impairment in transgenic Alzheimer mice requires cellular prion protein.

PMID:20573181

Progressive accumulation of amyloid-beta oligomers in Alzheimer's disease and in amyloid precursor protein transgenic mice is accompanied by selective alterations in synaptic scaffold proteins.

PMID:20811458

Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease.

PMID:20817278

Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease.

PMID:20818335

Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio.

PMID:20828565

An aminopeptidase from Streptomyces sp. KK565 degrades beta amyloid monomers, oligomers and fibrils.

PMID:20974225

Activation of nicotinic α(7) acetylcholine receptor enhances long term potentation in wild type mice but not in APP(swe)/PS1ΔE9 mice.

PMID:21113149

Reversing EphB2 depletion rescues cognitive functions in Alzheimer model.

PMID:21126803

Perlecan domain V inhibits α2 integrin-mediated amyloid-β neurotoxicity.

PMID:21163940

Interactome mapping suggests new mechanistic details underlying Alzheimer's disease.

PMID:2119582

Transforming growth factor-beta bound to soluble derivatives of the beta amyloid precursor protein of Alzheimer's disease.

PMID:21205198

Lysophosphatidylcholine modulates fibril formation of amyloid beta peptide.

PMID:21289173

Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-beta uptake.

PMID:21293490

Mediator is a transducer of amyloid-precursor-protein-dependent nuclear signalling.

PMID:21320494

Lipid matrix plays a role in Abeta fibril kinetics and morphology.

PMID:21527912

Extracellular phosphorylation of the amyloid β-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease.

PMID:21857966

WNT5A signaling contributes to Aβ-induced neuroinflammation and neurotoxicity.

PMID:21989385

Quantitative modelling of amyloidogenic processing and its influence by SORLA in Alzheimer's disease.

PMID:22036569

Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent β-amyloid generation.

PMID:22138302

Preferential interactions between ApoE-containing lipoproteins and Aβ revealed by a detection method that combines size exclusion chromatography with non-reducing gel-shift.

PMID:22179788

The extracellular chaperone clusterin sequesters oligomeric forms of the amyloid-β(1-40) peptide.

PMID:22198949

TLR2 is a primary receptor for Alzheimer's amyloid β peptide to trigger neuroinflammatory activation.

PMID:22200570

Effect of N-homocysteinylation on physicochemical and cytotoxic properties of amyloid β-peptide.

PMID:22406537

A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease.

PMID:22500019

Amyloid β (Aβ) peptide directly activates amylin-3 receptor subtype by triggering multiple intracellular signaling pathways.

PMID:22528093

Search for amyloid-binding proteins by affinity chromatography.

PMID:22584060

Dimeric structure of transmembrane domain of amyloid precursor protein in micellar environment.

PMID:22730553

Open-closed motion of Mint2 regulates APP metabolism.

PMID:22801501

A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.

PMID:22820466

Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons.

PMID:22944668

Antimicrobial activity of human islet amyloid polypeptides: an insight into amyloid peptides' connection with antimicrobial peptides.

PMID:23103738

A comparative analysis of the aggregation behavior of amyloid-β peptide variants.

PMID:23106396

Amyloid-β oligomers are sequestered by both intracellular and extracellular chaperones.

PMID:23152628

LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer's amyloid-β.

PMID:23164821

Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway.

PMID:23353684

Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via two distinct mechanisms.

PMID:23382219

Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.

PMID:23416305

Interaction between soluble Aβ-(1-40) monomer and Aβ-(1-42) fibrils probed by paramagnetic relaxation enhancement.

PMID:23525105

Transcriptional regulation of insulin-degrading enzyme modulates mitochondrial amyloid β (Aβ) peptide catabolism and functionality.

PMID:23551356

N-terminal domain of Pyrococcus furiosus l-asparaginase functions as a non-specific, stable, molecular chaperone.

PMID:23585889

Generation of amyloid-β is reduced by the interaction of calreticulin with amyloid precursor protein, presenilin and nicastrin.

PMID:23603391

NMR characterization of the interaction of GroEL with amyloid β as a model ligand.

PMID:23640054

Brain interstitial oligomeric amyloid β increases with age and is resistant to clearance from brain in a mouse model of Alzheimer's disease.

PMID:23907009

Isobavachalcone and bavachinin from Psoraleae Fructus modulate Aβ42 aggregation process through different mechanisms in vitro.

PMID:23921129

FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer's disease.

PMID:23973487

Two β-strands of RAGE participate in the recognition and transport of amyloid-β peptide across the blood brain barrier.

PMID:24012003

Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein.

PMID:24028865

Impact of the cellular prion protein on amyloid-β and 3PO-tau processing.

PMID:24052308

Human LilrB2 is a β-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model.

PMID:24065130

Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin.

PMID:24284412

Amyloid beta a4 precursor protein-binding family B member 1 (FE65) interactomics revealed synaptic vesicle glycoprotein 2A (SV2A) and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) as new binding proteins in the human brain.

PMID:24305806

Pharmacologic inhibition of ROCK2 suppresses amyloid-β production in an Alzheimer's disease mouse model.

PMID:24336208

Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease.

PMID:24499793

FKBP12 regulates the localization and processing of amyloid precursor protein in human cell lines.

PMID:24720730

The coexistence of an equal amount of Alzheimer's amyloid-β 40 and 42 forms structurally stable and toxic oligomers through a distinct pathway.

PMID:24867889

sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin.

PMID:24931469

Molecular basis of substrate recognition and degradation by human presequence protease.

PMID:25241761

Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.

PMID:25543257

Modeling an in-register, parallel "iowa" aβ fibril structure using solid-state NMR data from labeled samples with rosetta.

PMID:25620700

A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology.

PMID:25643321

Structural basis for amyloidogenic peptide recognition by sorLA.

PMID:25897080

Sequential Amyloid-β Degradation by the Matrix Metalloproteases MMP-2 and MMP-9.

PMID:25959826

Quantitative interaction proteomics of neurodegenerative disease proteins.

PMID:26005850

Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance.

PMID:26006083

The multidrug resistance pump ABCB1 is a substrate for the ubiquitin ligase NEDD4-1.

PMID:26138908

High-resolution NMR characterization of low abundance oligomers of amyloid-β without purification.

PMID:26200696

Dual pathways mediate β-amyloid stimulated glutathione release from astrocytes.

PMID:26496610

A human interactome in three quantitative dimensions organized by stoichiometries and abundances.

PMID:26618561

Direct High Affinity Interaction between Aβ42 and GSK3α Stimulates Hyperphosphorylation of Tau. A New Molecular Link in Alzheimer's Disease?

PMID:27853422

ROCK1 Is Associated with Alzheimer's Disease-Specific Plaques, as well as Enhances Autophagosome Formation But not Autophagic Aβ Clearance.

PMID:28008308

The Protective Role of microRNA-200c in Alzheimer's Disease Pathologies Is Induced by Beta Amyloid-Triggered Endoplasmic Reticulum Stress.

PMID:28164773

Apolipoprotein E-mediated Modulation of ADAM10 in Alzheimer's Disease.

PMID:28720718

Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson's disease.

PMID:28855300

An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function.

PMID:28882996

Fibril structure of amyloid-β(1-42) by cryo-electron microscopy.

PMID:29061364

Inflammatory microglia are glycolytic and iron retentive and typify the microglia in APP/PS1 mice.

PMID:29274751

Reduced expression of Na(+)/Ca(2+) exchangers is associated with cognitive deficits seen in Alzheimer's disease model mice.

PMID:29423001

Hypoxia increases amyloid-β level in exosomes by enhancing the interaction between CD147 and Hook1.

PMID:29518356

TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function.

PMID:29578633

Probing the Mint2 Protein-Protein Interaction Network Relevant to the Pathophysiology of Alzheimer's Disease.

PMID:29961672

miR-15b reduces amyloid-β accumulation in SH-SY5Y cell line through targetting NF-κB signaling and BACE1.

PMID:30086173

TMEM30A is a candidate interacting partner for the β-carboxyl-terminal fragment of amyloid-β precursor protein in endosomes.

PMID:30158114

TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer's disease.

PMID:30538620

Visualization of Alzheimer's Disease Related α-/β-/γ-Secretase Ternary Complex by Bimolecular Fluorescence Complementation Based Fluorescence Resonance Energy Transfer.

PMID:31413325

HENA, heterogeneous network-based data set for Alzheimer's disease.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33239400

Implications of Oligomeric Amyloid-Beta (oAβ(42)) Signaling through α7β2-Nicotinic Acetylcholine Receptors (nAChRs) on Basal Forebrain Cholinergic Neuronal Intrinsic Excitability and Cognitive Decline.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34446781

First identification of ITM2B interactome in the human retina.

PMID:35063084

Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration.

PMID:35914814

Chr21 protein-protein interactions: enrichment in proteins involved in intellectual disability, autism, and late-onset Alzheimer's disease.

PMID:35922511

A physical wiring diagram for the human immune system.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

PMID:7593229

Serine proteinase inhibitors in human skeletal muscle: expression of beta-amyloid protein precursor and alpha 1-antichymotrypsin in vivo and during myogenesis in vitro.

PMID:8626687

APP-BP1, a novel protein that binds to the carboxyl-terminal region of the amyloid precursor protein.

PMID:8855266

Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein.

PMID:8887653

The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein.

PMID:9211985

Association of human, rat, and rabbit apolipoprotein E with beta-amyloid.

PMID:9223340

Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease.

PMID:9228033

Interaction of apolipoprotein J-amyloid beta-peptide complex with low density lipoprotein receptor-related protein-2/megalin. A mechanism to prevent pathological accumulation of amyloid beta-peptide.

PMID:9338779

An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer's disease.

PMID:9461550

Fe65L2: a new member of the Fe65 protein family interacting with the intracellular domain of the Alzheimer's beta-amyloid precursor protein.

PMID:9737846

Solution structure of methionine-oxidized amyloid beta-peptide (1-40). Does oxidation affect conformational switching?

PMID:9774383

Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor.

Reactome:R-HSA-1296421

NLRP3 oligomerizes via NACHT domains

Reactome:R-HSA-2467665

AGRN binds Beta amyloid fibril via GAG chains

Reactome:R-HSA-379048

Liganded Gq/11-activating GPCRs act as GEFs for Gq/11

Reactome:R-HSA-380073

Liganded Gi-activating GPCR acts as a GEF for Gi

Reactome:R-HSA-391913

FPR2 binds FPR2 ligands

Reactome:R-HSA-481007

Exocytosis of platelet alpha granule contents

Reactome:R-HSA-5229111

AP4 transports APP from trans-Golgi network to endosome lumen

Reactome:R-HSA-5229132

AP4 binds APP

Reactome:R-HSA-5692495

BACE1 cleaves APP(18-770) to APP(18-671) and APP(672-770)

Reactome:R-HSA-6783332

APP(672-713),APP(672-711) translocate from endosome lumen to extracellular region

Reactome:R-HSA-749448

Liganded Gq-activating GPCRs bind inactive heterotrimeric Gq

Reactome:R-HSA-749452

The Ligand:GPCR:Gq complex dissociates

Reactome:R-HSA-749454

The Ligand:GPCR:Gi complex dissociates

Reactome:R-HSA-749456

Liganded Gi-activating GPCRs bind inactive heterotrimeric G-protein Gi

Reactome:R-HSA-844440

NLRP3 activation by elicitor proteins

Reactome:R-HSA-844610

NLRP3 recruits PYCARD (ASC) via a PYD-PYD interaction

Reactome:R-HSA-844612

PYCARD recruits procaspase-1 via CARD

Reactome:R-HSA-879411

Advanced glycosylation end product-specific receptor (AGER/RAGE) is a multiligand receptor

Reactome:R-HSA-8870710

APP gene expression

Reactome:R-HSA-8871494

SORL1 binds APP(18-770)

Reactome:R-HSA-8871506

SORL1 transports APP(18-770) from endosome lumen to Golgi lumen

Reactome:R-HSA-8952289

FAM20C phosphorylates FAM20C substrates

Reactome:R-HSA-9010034

ADAM10:Zn2+:TSPANs cleaves APP(18-770)

Reactome:R-HSA-9010091

APP translocates from plasma membrane to endosome lumen

Reactome:R-HSA-9010096

Gamma-secretase cleaves APP(672-770) to APP(672-711) and APP(672-713)

Reactome:R-HSA-9617595

SGTA binds mislocalized membrane protein

Reactome:R-HSA-976734

Amyloid fibrils have additional components

Reactome:R-HSA-977136

Amyloid precursor proteins form ordered fibrils

Reactome:R-HSA-9839072

HTRA2 degrades APP (Amyloid-beta precursor protein)

Reactome:R-NUL-997411

AGER binds rat ERK1/2

📚 Additional Documentation

Deep Research Bioreason

(APP-deep-research-bioreason.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:43 AM

Organism: Homo sapiens

Sequence:

MLPGLALLLLAAWTARALEVPTDGNAGLLAEPQIAMFCGRLNMHMNVQNGKWDSDPSGTKTCIDTKEGILQYCQEVYPELQITNVVEANQPVTIQNWCKRGRKQCKTHPHFVIPYRCLVGEFVSDALLVPDKCKFLHQERMDVCETHLHWHTVAKETCSEKSTNLHDYGMLLPCGIDKFRGVEFVCCPLAEESDNVDSADAEEDDSDVWWGGADTDYADGSEDKVVEVAEEEEVAEVEEEEADDDEDDEDGDEVEEEAEEPYEEATERTTSIATTTTTTTESVEEVVREVCSEQAETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVCGSAMSQSLLKTTQEPLARDPVKLPTTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKHRERMSQVMREWEEAERQAKNLPKADKKAVIQHFQEKVESLEQEAANERQQLVETHMARVEAMLNDRRRLALENYITALQAVPPRPRHVFNMLKKYVRAEQKDRQHTLKHFEHVRMVDPKKAAQIRSQVMTHLRVIYERMNQSLSLLYNVPAVAEEIQDEVDELLQKEQNYSDDVLANMISEPRISYGNDALMPSLTETKTTVELLPVNGEFSLDDLQPWHSFGADSVPANTENEVEPVDARPAADRGLTTRPGSGLTNIKTEEISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFEQMQN

Thinking Trace

I begin with the InterPro architecture and its order along the sequence. A broad family signature, IPR008155 (Amyloidogenic glycoprotein, residues 10–770), blankets almost the entire ectodomain-to-cytosolic tail region, indicating a canonical amyloid precursor–like topology. The N-terminal ectodomain is elaborated by several layered modules: IPR008154 (Amyloidogenic glycoprotein, extracellular domain, residues 24–189) establishes an extensive secreted/lumenal region that is primed for ligand capture and proteolysis. Within this region, IPR036454 (heparin-binding domain superfamily, residues 17–123) and IPR015849 (heparin-binding domain, residues 31–131) define a glycosaminoglycan-interacting surface, while IPR036669 (copper-binding domain superfamily, residues 124–189) and IPR011178 (copper-binding domain, residues 132–188) add a metal-binding fold that stabilizes the ectodomain and can modulate redox or conformational states. Together, these N-terminal modules create a polyvalent extracellular platform that binds heparin/heparan sulfate and coordinates copper, predisposing the protein to extracellular matrix engagement and regulated ectodomain shedding.

Midway through the sequence, IPR036880 (Pancreatic trypsin inhibitor Kunitz domain superfamily, residues 279–352) and its specific instance IPR002223 (Kunitz domain, residues 288–342), reinforced by IPR020901 (Kunitz conserved site, residues 319–337), introduce a protease-inhibitor–like module. This Kunitz architecture typically confers serine protease inhibition and often serves as a regulatory spacer that modulates pericellular proteolysis. Its presence causes the ectodomain to locally suppress or redirect protease activity, thereby controlling cleavage timing and producing defined soluble products.

Downstream, IPR036176 (E2 domain superfamily, residues 363–580) and IPR024329 (E2 domain, residues 367–565) define the classic E2 repeat that binds heparin/heparan sulfate and supports ectodomain folding and trafficking. This reinforces the earlier heparin-binding theme and further consolidates an extracellular adhesion and signaling hub.

Near the C-terminal region, IPR037071 (amyloid-beta peptide superfamily, residues 672–711) and IPR013803 (amyloid-beta peptide domain, residues 675–713) mark a cleavage-derived segment that can generate amyloidogenic peptides upon regulated intramembrane proteolysis. Immediately following, IPR019543 (beta-amyloid precursor protein C-terminal domain, residues 716–766) and IPR011993 (PH-like domain superfamily, residues 742–770) culminate in a cytosolic tail that directs intracellular signaling. This tail, reinforced by IPR019745 (intracellular domain conserved site, residues 756–763), is optimized for adaptor binding and endocytic routing; a PH-like fold favors interactions with membrane-proximal adaptors and trafficking machinery. The overall architecture therefore transitions from a large, ligand-rich ectodomain to a membrane anchor and a signaling-competent cytosolic tail.

From this domain architecture, I infer molecular functions. The heparin-binding and Kunitz modules cause high-affinity glycosaminoglycan engagement and localized protease regulation, respectively. The copper-binding fold stabilizes ectodomain structure and may tune redox-sensitive interactions. These features together necessitate multivalent protein binding and protease modulation. Thus, the minimal defensible molecular function is GO:0005515 protein binding, with the Kunitz core supporting a protease-inhibitor mechanism that shapes extracellular proteolysis and intracellular signaling via tail-mediated adaptor interactions.

These molecular activities feed directly into biological processes. The combination of heparin/heparan sulfate binding and copper/Kunitz-mediated protease control situates the protein in membrane-proximal trafficking and shedding pathways, which drive GO:0006468 protein processing. The C-terminal domain and PH-like fold drive adaptor-mediated internalization and signaling scaffolding, supporting GO:0006897 endocytosis and broader vesicle-mediated turnover. Collectively, this architecture orchestrates extracellular matrix engagement, regulated cleavage, and endocytic routing that collectively regulate cell-surface composition and signaling.

The cellular component is dictated by the topology: an extensive ectodomain, a single-pass membrane anchor, and a cytosolic tail establish a membrane-resident configuration. The presence of an intracellular signaling tail and trafficking motifs points to a plasma membrane pool and endocytic vesicles; therefore, the most parsimonious localization is GO:0016021 integral component of membrane, with enrichment at the cell surface and along endocytic routes.

Mechanistically, the protein operates as a membrane-tethered adhesion/signaling hub. The ectodomain binds heparin/heparan sulfate and coordinates copper to stabilize extracellular interactions; the Kunitz module tempers pericellular proteolysis; the E2 repeat and amyloid-beta–like segments govern ectodomain folding and regulated intramembrane proteolysis; and the cytosolic tail recruits adaptors to couple extracellular cues to endocytosis and signaling. I hypothesize that it transiently associates with heparan sulfate proteoglycans and extracellular matrix, undergoes sequential cleavages that yield soluble ectodomains and amyloid-beta–like peptides, and signals via its cytosolic tail through adaptor complexes that regulate endocytosis and membrane trafficking. Likely partners include membrane-proximal adaptors (e.g., PTB/PH-like–binding scaffolds), clathrin-associated endocytic machinery, and metal/redox cofactors that stabilize its ectodomain and cleavage-dependent pathway.

Functional Summary

A single-pass membrane glycoprotein that assembles a large extracellular platform for glycosaminoglycan engagement and regulated proteolysis, coupled to a cytosolic tail that recruits trafficking and signaling adaptors. Its ectodomain binds heparin and coordinates copper to stabilize matrix interactions, while a built-in Kunitz module modulates pericellular protease activity and an E2 repeat supports folding and shedding. Sequential cleavage events yield soluble ectodomains and amyloidogenic peptides, linking extracellular adhesion to intracellular signaling. The cytosolic tail and PH-like fold route the protein through endocytic pathways and membrane-associated signaling hubs, integrating cell-surface engagement with vesicle-mediated processing.

UniProt Summary

Precursor of amyloid-beta precursor protein.

InterPro Domains

Amyloidogenic glycoprotein (IPR008155, family) — residues 10-770
Amyloidogenic glycoprotein, heparin-binding domain superfamily (IPR036454, homologous_superfamily) — residues 17-123
Amyloidogenic glycoprotein, extracellular (IPR008154, domain) — residues 24-189
Amyloidogenic glycoprotein, heparin-binding (IPR015849, domain) — residues 31-131
Amyloidogenic glycoprotein, copper-binding domain superfamily (IPR036669, homologous_superfamily) — residues 124-189
Amyloidogenic glycoprotein, copper-binding (IPR011178, domain) — residues 132-188
Amyloidogenic glycoprotein, copper-binding domain conserved site (IPR019744, conserved_site) — residues 181-188
Pancreatic trypsin inhibitor Kunitz domain superfamily (IPR036880, homologous_superfamily) — residues 279-352
Pancreatic trypsin inhibitor Kunitz domain (IPR002223, domain) — residues 288-342
Proteinase inhibitor I2, Kunitz, conserved site (IPR020901, conserved_site) — residues 319-337
E2 domain superfamily (IPR036176, homologous_superfamily) — residues 363-580
Amyloidogenic glycoprotein, E2 domain (IPR024329, domain) — residues 367-565
Amyloidogenic glycoprotein, amyloid-beta peptide superfamily (IPR037071, homologous_superfamily) — residues 672-711
Amyloidogenic glycoprotein, amyloid-beta peptide (IPR013803, domain) — residues 675-713
Beta-amyloid precursor protein C-terminal (IPR019543, domain) — residues 716-766
PH-like domain superfamily (IPR011993, homologous_superfamily) — residues 742-770
Amyloidogenic glycoprotein, intracellular domain, conserved site (IPR019745, conserved_site) — residues 756-763

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), molecular function regulator activity (GO:0098772), enzyme regulator activity (GO:0030234), small molecule binding (GO:0036094), sulfur compound binding (GO:1901681), hormone binding (GO:0042562), molecular function inhibitor activity (GO:0140678), molecular function activator activity (GO:0140677), protein-containing complex binding (GO:0044877), signaling receptor regulator activity (GO:0030545), chromatin binding (GO:0003682), amide binding (GO:0033218), ion binding (GO:0043167), carbohydrate derivative binding (GO:0097367), protein binding (GO:0005515), heparan sulfate proteoglycan binding (GO:0043395), chaperone binding (GO:0051087), proteoglycan binding (GO:0043394), identical protein binding (GO:0042802), anion binding (GO:0043168), cell adhesion molecule binding (GO:0050839), integrin binding (GO:0005178), enzyme inhibitor activity (GO:0004857), signaling receptor activator activity (GO:0030546), apolipoprotein binding (GO:0034185), signaling receptor binding (GO:0005102), insulin receptor binding (GO:0005158), organic acid binding (GO:0043177), protein dimerization activity (GO:0046983), glycosaminoglycan binding (GO:0005539), peptide hormone binding (GO:0017046), peptide binding (GO:0042277), protein domain specific binding (GO:0019904), neurotransmitter receptor regulator activity (GO:0099602), enzyme binding (GO:0019899), peptidase regulator activity (GO:0061134), receptor ligand activity (GO:0048018), endopeptidase regulator activity (GO:0061135), protein heterodimerization activity (GO:0046982), carboxylic acid binding (GO:0031406), ephrin receptor binding (GO:0046875), protein homodimerization activity (GO:0042803), acetylcholine receptor regulator activity (GO:0030548), peptidase inhibitor activity (GO:0030414), G protein-coupled receptor binding (GO:0001664), endopeptidase inhibitor activity (GO:0004866), frizzled binding (GO:0005109), chemoattractant activity (GO:0042056), serine-type endopeptidase inhibitor activity (GO:0004867)

Biological Process: biological_process (GO:0008150), signaling (GO:0023052), biological regulation (GO:0065007), response to stimulus (GO:0050896), biological process involved in interspecies interaction between organisms (GO:0044419), negative regulation of biological process (GO:0048519), positive regulation of biological process (GO:0048518), regulation of biological process (GO:0050789), multicellular organismal process (GO:0032501), developmental process (GO:0032502), cellular process (GO:0009987), metabolic process (GO:0008152), immune system process (GO:0002376), anatomical structure development (GO:0048856), negative regulation of signaling (GO:0023057), immune response (GO:0006955), positive regulation of multicellular organismal process (GO:0051240), positive regulation of immune system process (GO:0002684), cellular component organization or biogenesis (GO:0071840), regulation of multicellular organismal process (GO:0051239), positive regulation of transport (GO:0051050), negative regulation of metabolic process (GO:0009892), regulation of biological quality (GO:0065008), regulation of cellular process (GO:0050794), regulation of response to stimulus (GO:0048583), cellular response to stimulus (GO:0051716), negative regulation of cellular process (GO:0048523), regulation of locomotion (GO:0040012), cellular developmental process (GO:0048869), positive regulation of response to stimulus (GO:0048584), regulation of metabolic process (GO:0019222), immune effector process (GO:0002252), regulation of molecular function (GO:0065009), cell communication (GO:0007154), positive regulation of cellular process (GO:0048522), response to external stimulus (GO:0009605), response to chemical (GO:0042221), leukocyte activation (GO:0045321), nitrogen compound metabolic process (GO:0006807), negative regulation of multicellular organismal process (GO:0051241), regulation of developmental process (GO:0050793), response to biotic stimulus (GO:0009607), response to endogenous stimulus (GO:0009719), positive regulation of locomotion (GO:0040017), cell death (GO:0008219), regulation of signaling (GO:0023051), response to other organism (GO:0051707), signal transduction (GO:0007165), positive regulation of signaling (GO:0023056), cell activation (GO:0001775), multicellular organism development (GO:0007275), regulation of localization (GO:0032879), regulation of immune system process (GO:0002682), organic substance metabolic process (GO:0071704), system process (GO:0003008), positive regulation of metabolic process (GO:0009893), response to stress (GO:0006950), positive regulation of developmental process (GO:0051094), negative regulation of response to stimulus (GO:0048585), primary metabolic process (GO:0044238), behavior (GO:0007610), cellular component biogenesis (GO:0044085), regulation of cell motility (GO:2000145), negative regulation of cellular component organization (GO:0051129), response to external biotic stimulus (GO:0043207), negative regulation of protein localization (GO:1903828), regulation of response to stress (GO:0080134), regulation of system process (GO:0044057), regulation of signal transduction (GO:0009966), regulation of macromolecule metabolic process (GO:0060255), regulation of response to external stimulus (GO:0032101), regulation of vesicle-mediated transport (GO:0060627), regulation of cytokine production (GO:0001817), regulation of cellular component biogenesis (GO:0044087), negative regulation of blood circulation (GO:1903523), learning or memory (GO:0007611), negative regulation of macromolecule metabolic process (GO:0010605), G protein-coupled receptor signaling pathway (GO:0007186), regulation of membrane potential (GO:0042391), positive regulation of nitrogen compound metabolic process (GO:0051173), positive regulation of cell differentiation (GO:0045597), regulation of catalytic activity (GO:0050790), regulation of synaptic plasticity (GO:0048167), negative regulation of nitrogen compound metabolic process (GO:0051172), positive regulation of molecular function (GO:0044093), positive regulation of protein localization (GO:1903829), positive regulation of macromolecule metabolic process (GO:0010604), leukocyte activation involved in inflammatory response (GO:0002269), regulation of cellular localization (GO:0060341), negative regulation of cell population proliferation (GO:0008285), protein metabolic process (GO:0019538), regulation of cellular response to stress (GO:0080135), response to oxygen-containing compound (GO:1901700), glial cell activation (GO:0061900), macromolecule metabolic process (GO:0043170), positive regulation of cell motility (GO:2000147), innate immune response (GO:0045087), positive regulation of biosynthetic process (GO:0009891), defense response to other organism (GO:0098542), regulation of response to biotic stimulus (GO:0002831), regulation of immune response (GO:0050776), regulation of cell population proliferation (GO:0042127), regulation of cell death (GO:0010941), response to nitrogen compound (GO:1901698), positive regulation of cellular metabolic process (GO:0031325), regulation of DNA-binding transcription factor activity (GO:0051090), humoral immune response (GO:0006959), regulation of cellular metabolic process (GO:0031323), positive regulation of cell communication (GO:0010647), negative regulation of biosynthetic process (GO:0009890), nervous system process (GO:0050877), regulation of trans-synaptic signaling (GO:0099177), regulation of primary metabolic process (GO:0080090), negative regulation of signal transduction (GO:0009968), positive regulation of cell death (GO:0010942), positive regulation of response to external stimulus (GO:0032103), programmed cell death (GO:0012501), negative regulation of cell death (GO:0060548), regulation of signaling receptor activity (GO:0010469), regulation of leukocyte migration (GO:0002685), cell development (GO:0048468), cell differentiation (GO:0030154), positive regulation of response to endoplasmic reticulum stress (GO:1905898), system development (GO:0048731), cellular response to endogenous stimulus (GO:0071495), regulation of synapse structure or activity (GO:0050803), regulation of binding (GO:0051098), neuron death (GO:0070997), regulation of catabolic process (GO:0009894), positive regulation of synaptic transmission (GO:0050806), regulation of nitrogen compound metabolic process (GO:0051171), regulation of cell differentiation (GO:0045595), cellular component organization (GO:0016043), positive regulation of cytokine production (GO:0001819), positive regulation of defense response (GO:0031349), regulation of cellular component organization (GO:0051128), positive regulation of signal transduction (GO:0009967), negative regulation of cell communication (GO:0010648), regulation of transport (GO:0051049), organonitrogen compound metabolic process (GO:1901564), positive regulation of carbohydrate metabolic process (GO:0045913), intracellular signal transduction (GO:0035556), regulation of chemotaxis (GO:0050920), regulation of transporter activity (GO:0032409), defense response (GO:0006952), regulation of transmembrane transport (GO:0034762), positive regulation of cellular component organization (GO:0051130), negative regulation of cellular metabolic process (GO:0031324), response to organic substance (GO:0010033), positive regulation of leukocyte migration (GO:0002687), regulation of amyloid-beta clearance (GO:1900221), positive regulation of small molecule metabolic process (GO:0062013), regulation of cell communication (GO:0010646), cellular response to chemical stimulus (GO:0070887), cell activation involved in immune response (GO:0002263), regulation of biosynthetic process (GO:0009889), regulation of small molecule metabolic process (GO:0062012), myeloid leukocyte activation (GO:0002274), positive regulation of protein transport (GO:0051222), positive regulation of endocytosis (GO:0045807), positive regulation of chemotaxis (GO:0050921), positive regulation of catabolic process (GO:0009896), regulation of tumor necrosis factor superfamily cytokine production (GO:1903555), cell projection organization (GO:0030030), positive regulation of long-term synaptic potentiation (GO:1900273), regulation of synapse organization (GO:0050807), regulation of macromolecule biosynthetic process (GO:0010556), regulation of protein metabolic process (GO:0051246), positive regulation of establishment of protein localization (GO:1904951), astrocyte activation (GO:0048143), regulation of G protein-coupled receptor signaling pathway (GO:0008277), regulation of stress-activated protein kinase signaling cascade (GO:0070302), glial cell differentiation (GO:0010001), regulation of interleukin-6 production (GO:0032675), regulation of protein binding (GO:0043393), amyloid fibril formation (GO:1990000), regulation of neurotransmitter receptor activity (GO:0099601), regulation of gene expression (GO:0010468), regulation of response to endoplasmic reticulum stress (GO:1905897), regulation of cellular response to oxidative stress (GO:1900407), regulation of nucleotide metabolic process (GO:0006140), regulation of supramolecular fiber organization (GO:1902903), regulation of protein transport (GO:0051223), regulation of oxidative stress-induced cell death (GO:1903201), positive regulation of supramolecular fiber organization (GO:1902905), positive regulation of interleukin-1 production (GO:0032732), regulation of response to oxidative stress (GO:1902882), positive regulation of nucleotide metabolic process (GO:0045981), positive regulation of mononuclear cell migration (GO:0071677), positive regulation of cell migration (GO:0030335), positive regulation of intracellular signal transduction (GO:1902533), regulation of leukocyte chemotaxis (GO:0002688), positive regulation of catalytic activity (GO:0043085), positive regulation of reactive oxygen species metabolic process (GO:2000379), lipoprotein metabolic process (GO:0042157), positive regulation of excitatory postsynaptic potential (GO:2000463), cellular response to oxygen-containing compound (GO:1901701), negative regulation of gene expression (GO:0010629), positive regulation of neuron death (GO:1901216), cellular response to organonitrogen compound (GO:0071417), leukocyte differentiation (GO:0002521), regulation of innate immune response (GO:0045088), regulation of cell projection organization (GO:0031344), regulation of reactive oxygen species metabolic process (GO:2000377), cellular response to organic substance (GO:0071310), regulation of long-term synaptic depression (GO:1900452), regulation of monoatomic ion transmembrane transport (GO:0034765), modulation of chemical synaptic transmission (GO:0050804), positive regulation of G protein-coupled receptor signaling pathway (GO:0045745), positive regulation of interleukin-6 production (GO:0032755), cellular response to nitrogen compound (GO:1901699), regulation of neuron death (GO:1901214), regulation of pattern recognition receptor signaling pathway (GO:0062207), regulation of Wnt signaling pathway (GO:0030111), learning (GO:0007612), regulation of protein localization (GO:0032880), positive regulation of leukocyte chemotaxis (GO:0002690), myeloid cell differentiation (GO:0030099), memory (GO:0007613), positive regulation of macromolecule biosynthetic process (GO:0010557), neurogenesis (GO:0022008), regulation of generation of precursor metabolites and energy (GO:0043467), negative regulation of organelle organization (GO:0010639), positive regulation of RNA metabolic process (GO:0051254), inflammatory response (GO:0006954), neuron apoptotic process (GO:0051402), positive regulation of glycolytic process (GO:0045821), regulation of cellular biosynthetic process (GO:0031326), apoptotic process (GO:0006915), regulation of nucleobase-containing compound metabolic process (GO:0019219), positive regulation of protein catabolic process (GO:0045732), regulation of organelle organization (GO:0033043), regulation of transmembrane transporter activity (GO:0022898), regulation of transferase activity (GO:0051338), negative regulation of cell projection organization (GO:0031345), adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), cell junction organization (GO:0034330), positive regulation of cellular biosynthetic process (GO:0031328), supramolecular fiber organization (GO:0097435), response to peptide (GO:1901652), regulation of defense response (GO:0031347), regulation of neuron differentiation (GO:0045664), antimicrobial humoral response (GO:0019730), regulation of chemokine production (GO:0032642), regulation of programmed cell death (GO:0043067), regulation of establishment of protein localization (GO:0070201), modulation of excitatory postsynaptic potential (GO:0098815), positive regulation of oxidative stress-induced cell death (GO:1903209), positive regulation of receptor-mediated endocytosis (GO:0048260), regulation of cell migration (GO:0030334), positive regulation of type II interferon production (GO:0032729), regulation of blood circulation (GO:1903522), neuron development (GO:0048666), second-messenger-mediated signaling (GO:0019932), cellular component assembly (GO:0022607), negative regulation of protein localization to nucleus (GO:1900181), nervous system development (GO:0007399), positive regulation of inflammatory response (GO:0050729), regulation of nervous system process (GO:0031644), regulation of neuronal synaptic plasticity (GO:0048168), central nervous system development (GO:0007417), negative regulation of Wnt signaling pathway (GO:0030178), protein-containing complex organization (GO:0043933), regulation of RNA metabolic process (GO:0051252), regulation of mononuclear cell migration (GO:0071675), negative regulation of cellular biosynthetic process (GO:0031327), microglial cell activation (GO:0001774), regulation of long-term synaptic potentiation (GO:1900271), negative regulation of nucleobase-containing compound metabolic process (GO:0045934), positive regulation of DNA-binding transcription factor activity (GO:0051091), regulation of endocytosis (GO:0030100), hemopoiesis (GO:0030097), cognition (GO:0050890), negative regulation of neuron death (GO:1901215), positive regulation of nitric oxide metabolic process (GO:1904407), regulation of carbohydrate catabolic process (GO:0043470), positive regulation of phosphorus metabolic process (GO:0010562), positive regulation of neuron differentiation (GO:0045666), regulation of protein catabolic process (GO:0042176), positive regulation of chemokine production (GO:0032722), regulation of hydrolase activity (GO:0051336), positive regulation of programmed cell death (GO:0043068), regulation of cell junction assembly (GO:1901888), positive regulation of tumor necrosis factor superfamily cytokine production (GO:1903557), macrophage activation (GO:0042116), regulation of type II interferon production (GO:0032649), glial cell development (GO:0021782), positive regulation of gene expression (GO:0010628), regulation of carbohydrate metabolic process (GO:0006109), regulation of interleukin-1 production (GO:0032652), positive regulation of binding (GO:0051099), positive regulation of nucleobase-containing compound metabolic process (GO:0045935), regulation of nitric oxide metabolic process (GO:0080164), response to organonitrogen compound (GO:0010243), regulation of inflammatory response (GO:0050727), positive regulation of protein metabolic process (GO:0051247), positive regulation of cellular catabolic process (GO:0031331), negative regulation of macromolecule biosynthetic process (GO:0010558), regulation of monoatomic ion transport (GO:0043269), regulation of cellular catabolic process (GO:0031329), negative regulation of RNA metabolic process (GO:0051253), regulation of intracellular signal transduction (GO:1902531), regulation of phosphorus metabolic process (GO:0051174), neuron differentiation (GO:0030182), regulation of long-term neuronal synaptic plasticity (GO:0048169), regulation of purine nucleotide metabolic process (GO:1900542), myeloid cell development (GO:0061515), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), regulation of apoptotic process (GO:0042981), positive regulation of protein binding (GO:0032092), positive regulation of phosphate metabolic process (GO:0045937), regulation of RNA biosynthetic process (GO:2001141), regulation of monoatomic ion transmembrane transporter activity (GO:0032412), regulation of neuron apoptotic process (GO:0043523), positive regulation of NF-kappaB transcription factor activity (GO:0051092), calcium-mediated signaling (GO:0019722), positive regulation of membrane protein ectodomain proteolysis (GO:0051044), negative regulation of miRNA metabolic process (GO:2000629), regulation of synapse assembly (GO:0051963), regulation of kinase activity (GO:0043549), positive regulation of RNA biosynthetic process (GO:1902680), regulation of monoatomic cation transmembrane transport (GO:1904062), myeloid leukocyte differentiation (GO:0002573), positive regulation of protein modification process (GO:0031401), positive regulation of interleukin-1 beta production (GO:0032731), regulation of stress-activated MAPK cascade (GO:0032872), regulation of receptor binding (GO:1900120), positive regulation of tumor necrosis factor production (GO:0032760), regulation of MAPK cascade (GO:0043408), positive regulation of apoptotic process (GO:0043065), regulation of receptor-mediated endocytosis (GO:0048259), positive regulation of transferase activity (GO:0051347), regulation of plasma membrane bounded cell projection organization (GO:0120035), regulation of NIK/NF-kappaB signaling (GO:1901222), regulation of lymphocyte migration (GO:2000401), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), regulation of oxidative stress-induced neuron death (GO:1903203), plasma membrane bounded cell projection organization (GO:0120036), positive regulation of NIK/NF-kappaB signaling (GO:1901224), gliogenesis (GO:0042063), cellular response to peptide (GO:1901653), neuron projection development (GO:0031175), positive regulation of superoxide anion generation (GO:0032930), synapse organization (GO:0050808), regulation of tumor necrosis factor production (GO:0032680), regulation of monocyte chemotaxis (GO:0090025), regulation of toll-like receptor signaling pathway (GO:0034121), negative regulation of mitochondrion organization (GO:0010823), neuroinflammatory response (GO:0150076), regulation of proteolysis (GO:0030162), regulation of mitochondrion organization (GO:0010821), protein-containing complex assembly (GO:0065003), astrocyte development (GO:0014002), regulation of peptidase activity (GO:0052547), positive regulation of lymphocyte migration (GO:2000403), regulation of interleukin-1 beta production (GO:0032651), positive regulation of nitric oxide biosynthetic process (GO:0045429), positive regulation of receptor internalization (GO:0002092), positive regulation of monocyte chemotaxis (GO:0090026), regulation of amyloid precursor protein catabolic process (GO:1902991), positive regulation of purine nucleotide metabolic process (GO:1900544), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), positive regulation of amyloid precursor protein catabolic process (GO:1902993), positive regulation of MAPK cascade (GO:0043410), generation of neurons (GO:0048699), positive regulation of hydrolase activity (GO:0051345), negative regulation of canonical Wnt signaling pathway (GO:0090090), negative regulation of RNA biosynthetic process (GO:1902679), regulation of protein localization to nucleus (GO:1900180), regulation of presynapse organization (GO:0099174), regulation of canonical Wnt signaling pathway (GO:0060828), positive regulation of neuron apoptotic process (GO:0043525), regulation of glycolytic process (GO:0006110), regulation of postsynapse organization (GO:0099175), regulation of protein modification process (GO:0031399), regulation of superoxide metabolic process (GO:0090322), regulation of postsynaptic neurotransmitter receptor activity (GO:0098962), regulation of membrane protein ectodomain proteolysis (GO:0051043), regulation of DNA-templated transcription (GO:0006355), regulation of amyloid fibril formation (GO:1905906), regulation of phosphate metabolic process (GO:0019220), regulation of NMDA receptor activity (GO:2000310), positive regulation of proteolysis (GO:0045862), response to amyloid-beta (GO:1904645), regulation of nitric oxide biosynthetic process (GO:0045428), regulation of miRNA metabolic process (GO:2000628), associative learning (GO:0008306), astrocyte differentiation (GO:0048708), positive regulation of stress-activated protein kinase signaling cascade (GO:0070304), regulation of superoxide anion generation (GO:0032928), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to amyloid-beta (GO:1904646), positive regulation of peptidase activity (GO:0010952), regulation of endopeptidase activity (GO:0052548), regulation of protein kinase activity (GO:0045859), positive regulation of receptor binding (GO:1900122), regulation of receptor internalization (GO:0002090), protein complex oligomerization (GO:0051259), positive regulation of nucleic acid-templated transcription (GO:1903508), regulation of T cell migration (GO:2000404), positive regulation of phosphorylation (GO:0042327), positive regulation of ATP metabolic process (GO:1903580), positive regulation of protein phosphorylation (GO:0001934), positive regulation of protein acetylation (GO:1901985), positive regulation of stress-activated MAPK cascade (GO:0032874), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of kinase activity (GO:0033674), positive regulation of T cell migration (GO:2000406), regulation of ATP metabolic process (GO:1903578), regulation of cation channel activity (GO:2001257), regulation of histone modification (GO:0031056), neuron projection organization (GO:0106027), negative regulation of miRNA transcription (GO:1902894), regulation of protein acetylation (GO:1901983), positive regulation of histone modification (GO:0031058), regulation of protein phosphorylation (GO:0001932), regulation of dendritic spine maintenance (GO:1902950), negative regulation of DNA-templated transcription (GO:0045892), regulation of nucleic acid-templated transcription (GO:1903506), positive regulation of MAP kinase activity (GO:0043406), regulation of miRNA transcription (GO:1902893), regulation of ERK1 and ERK2 cascade (GO:0070372), regulation of phosphorylation (GO:0042325), regulation of JNK cascade (GO:0046328), negative regulation of nucleic acid-templated transcription (GO:1903507), macrophage differentiation (GO:0030225), regulation of presynapse assembly (GO:1905606), positive regulation of histone acetylation (GO:0035066), regulation of protein serine/threonine kinase activity (GO:0071900), positive regulation of peptidyl-serine phosphorylation (GO:0033138), negative regulation of transcription by RNA polymerase II (GO:0000122), protein tetramerization (GO:0051262), regulation of peptidyl-threonine phosphorylation (GO:0010799), positive regulation of peptidyl-tyrosine phosphorylation (GO:0050731), regulation of cysteine-type endopeptidase activity (GO:2000116), protein homooligomerization (GO:0051260), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of protein tyrosine kinase activity (GO:0061097), positive regulation of JNK cascade (GO:0046330), regulation of peptidyl-tyrosine phosphorylation (GO:0050730), positive regulation of endopeptidase activity (GO:0010950), positive regulation of peptidyl-lysine acetylation (GO:2000758), regulation of peptidyl-serine phosphorylation (GO:0033135), protein trimerization (GO:0070206), regulation of peptidyl-lysine acetylation (GO:2000756), positive regulation of protein kinase activity (GO:0045860), regulation of histone acetylation (GO:0035065), positive regulation of peptidyl-threonine phosphorylation (GO:0010800), regulation of MAP kinase activity (GO:0043405), positive regulation of cysteine-type endopeptidase activity (GO:2001056), regulation of cysteine-type endopeptidase activity involved in apoptotic process (GO:0043281), positive regulation of protein serine/threonine kinase activity (GO:0071902), positive regulation of protein tyrosine kinase activity (GO:0061098), positive regulation of cysteine-type endopeptidase activity involved in apoptotic process (GO:0043280)

Cellular Component: cellular_component (GO:0005575), cellular anatomical entity (GO:0110165), protein-containing complex (GO:0032991), cell body (GO:0044297), cell surface (GO:0009986), perinuclear region of cytoplasm (GO:0048471), cell junction (GO:0030054), organelle subcompartment (GO:0031984), dendritic shaft (GO:0043198), envelope (GO:0031975), postsynapse (GO:0098794), receptor complex (GO:0043235), membrane-enclosed lumen (GO:0031974), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), cell projection (GO:0042995), membrane (GO:0016020), cytosol (GO:0005829), presynapse (GO:0098793), cell periphery (GO:0071944), protein-lipid complex (GO:0032994), extracellular space (GO:0005615), somatodendritic compartment (GO:0036477), cytoplasm (GO:0005737), endomembrane system (GO:0012505), extracellular region (GO:0005576), plasma membrane bounded cell projection (GO:0120025), cytoplasmic vesicle (GO:0031410), intracellular organelle (GO:0043229), endosome (GO:0005768), synapse (GO:0045202), Golgi apparatus subcompartment (GO:0098791), Golgi apparatus (GO:0005794), membrane-bounded organelle (GO:0043227), plasma membrane (GO:0005886), organelle membrane (GO:0031090), organelle envelope (GO:0031967), secretory granule (GO:0030141), extracellular organelle (GO:0043230), transport vesicle (GO:0030133), vacuole (GO:0005773), plasma lipoprotein particle (GO:0034358), dendritic spine (GO:0043197), mitochondrion (GO:0005739), organelle lumen (GO:0043233), endoplasmic reticulum (GO:0005783), nuclear envelope (GO:0005635), membrane microdomain (GO:0098857), dendritic tree (GO:0097447), lipoprotein particle (GO:1990777), extracellular exosome (GO:0070062), cytoplasmic vesicle lumen (GO:0060205), membrane raft (GO:0045121), endoplasmic reticulum lumen (GO:0005788), lytic vacuole (GO:0000323), vesicle lumen (GO:0031983), secretory vesicle (GO:0099503), trans-Golgi network membrane (GO:0032588), triglyceride-rich plasma lipoprotein particle (GO:0034385), platelet alpha granule (GO:0031091), trans-Golgi network (GO:0005802), dendrite (GO:0030425), exocytic vesicle (GO:0070382), early endosome (GO:0005769), endosome lumen (GO:0031904), intracellular organelle lumen (GO:0070013), intracellular membrane-bounded organelle (GO:0043231), organelle envelope lumen (GO:0031970), high-density lipoprotein particle (GO:0034364), secretory granule lumen (GO:0034774), nuclear envelope lumen (GO:0005641), Golgi lumen (GO:0005796), extracellular membrane-bounded organelle (GO:0065010), neuron projection (GO:0043005), vesicle (GO:0031982), very-low-density lipoprotein particle (GO:0034361), extracellular vesicle (GO:1903561), neuron spine (GO:0044309), lysosome (GO:0005764), intracellular vesicle (GO:0097708), platelet alpha granule lumen (GO:0031093), nucleus (GO:0005634)

Generated by BioReason

Deep Research Bioreason Rl

(APP-deep-research-bioreason-rl.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:43 AM

Organism: Homo sapiens

Sequence:

MLPGLALLLLAAWTARALEVPTDGNAGLLAEPQIAMFCGRLNMHMNVQNGKWDSDPSGTKTCIDTKEGILQYCQEVYPELQITNVVEANQPVTIQNWCKRGRKQCKTHPHFVIPYRCLVGEFVSDALLVPDKCKFLHQERMDVCETHLHWHTVAKETCSEKSTNLHDYGMLLPCGIDKFRGVEFVCCPLAEESDNVDSADAEEDDSDVWWGGADTDYADGSEDKVVEVAEEEEVAEVEEEEADDDEDDEDGDEVEEEAEEPYEEATERTTSIATTTTTTTESVEEVVREVCSEQAETGPCRAMISRWYFDVTEGKCAPFFYGGCGGNRNNFDTEEYCMAVCGSAMSQSLLKTTQEPLARDPVKLPTTAASTPDAVDKYLETPGDENEHAHFQKAKERLEAKHRERMSQVMREWEEAERQAKNLPKADKKAVIQHFQEKVESLEQEAANERQQLVETHMARVEAMLNDRRRLALENYITALQAVPPRPRHVFNMLKKYVRAEQKDRQHTLKHFEHVRMVDPKKAAQIRSQVMTHLRVIYERMNQSLSLLYNVPAVAEEIQDEVDELLQKEQNYSDDVLANMISEPRISYGNDALMPSLTETKTTVELLPVNGEFSLDDLQPWHSFGADSVPANTENEVEPVDARPAADRGLTTRPGSGLTNIKTEEISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFEQMQN

Thinking Trace

Functional Summary

UniProt Summary

Precursor of amyloid-beta precursor protein.

InterPro Domains

Amyloidogenic glycoprotein (IPR008155, family) — residues 10-770
Amyloidogenic glycoprotein, heparin-binding domain superfamily (IPR036454, homologous_superfamily) — residues 17-123
Amyloidogenic glycoprotein, extracellular (IPR008154, domain) — residues 24-189
Amyloidogenic glycoprotein, heparin-binding (IPR015849, domain) — residues 31-131
Amyloidogenic glycoprotein, copper-binding domain superfamily (IPR036669, homologous_superfamily) — residues 124-189
Amyloidogenic glycoprotein, copper-binding (IPR011178, domain) — residues 132-188
Amyloidogenic glycoprotein, copper-binding domain conserved site (IPR019744, conserved_site) — residues 181-188
Pancreatic trypsin inhibitor Kunitz domain superfamily (IPR036880, homologous_superfamily) — residues 279-352
Pancreatic trypsin inhibitor Kunitz domain (IPR002223, domain) — residues 288-342
Proteinase inhibitor I2, Kunitz, conserved site (IPR020901, conserved_site) — residues 319-337
E2 domain superfamily (IPR036176, homologous_superfamily) — residues 363-580
Amyloidogenic glycoprotein, E2 domain (IPR024329, domain) — residues 367-565
Amyloidogenic glycoprotein, amyloid-beta peptide superfamily (IPR037071, homologous_superfamily) — residues 672-711
Amyloidogenic glycoprotein, amyloid-beta peptide (IPR013803, domain) — residues 675-713
Beta-amyloid precursor protein C-terminal (IPR019543, domain) — residues 716-766
PH-like domain superfamily (IPR011993, homologous_superfamily) — residues 742-770
Amyloidogenic glycoprotein, intracellular domain, conserved site (IPR019745, conserved_site) — residues 756-763

GO Terms

Generated by BioReason

Deep Research Falcon

(APP-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2026-03-06T02:46:51.330324'
end_time: '2026-03-06T02:59:06.425305'
duration_seconds: 735.1
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: APP
gene_symbol: APP
uniprot_accession: P05067
protein_description: 'RecName: Full=Amyloid-beta precursor protein {ECO:0000312|HGNC:HGNC:620};
Short=APP {ECO:0000312|HGNC:HGNC:620}; AltName: Full=ABPP; AltName: Full=APPI;
AltName: Full=Alzheimer disease amyloid A4 protein homolog; AltName: Full=Alzheimer
disease amyloid protein; AltName: Full=Amyloid precursor protein {ECO:0000305};
AltName: Full=Amyloid-beta (A4) precursor protein {ECO:0000250|UniProtKB:P12023};
AltName: Full=Amyloid-beta A4 protein; AltName: Full=Cerebral vascular amyloid
peptide; Short=CVAP; AltName: Full=PreA4; AltName: Full=Protease nexin-II; Short=PN-II;
Contains: RecName: Full=N-APP; Contains: RecName: Full=Soluble APP-alpha {ECO:0000303|PubMed:10656250};
Short=S-APP-alpha {ECO:0000303|PubMed:10656250}; Contains: RecName: Full=Soluble
APP-beta {ECO:0000303|PubMed:10656250}; Short=S-APP-beta {ECO:0000303|PubMed:10656250};
Contains: RecName: Full=C99; AltName: Full=Beta-secretase C-terminal fragment
{ECO:0000303|PubMed:10656250}; Short=Beta-CTF {ECO:0000303|PubMed:10656250}; Contains:
RecName: Full=Amyloid-beta protein 42 {ECO:0000303|PubMed:8886002}; Short=Abeta42;
AltName: Full=Beta-APP42; Contains: RecName: Full=Amyloid-beta protein 40 {ECO:0000303|PubMed:8886002};
Short=Abeta40; AltName: Full=Beta-APP40; Contains: RecName: Full=C83; AltName:
Full=Alpha-secretase C-terminal fragment {ECO:0000303|PubMed:10656250}; Short=Alpha-CTF
{ECO:0000303|PubMed:10656250}; Contains: RecName: Full=P3(42); Contains: RecName:
Full=P3(40); Contains: RecName: Full=C80; Contains: RecName: Full=Gamma-secretase
C-terminal fragment 59; AltName: Full=Amyloid intracellular domain 59; Short=AICD-59;
Short=AID(59); AltName: Full=Gamma-CTF(59); Contains: RecName: Full=Gamma-secretase
C-terminal fragment 57; AltName: Full=Amyloid intracellular domain 57; Short=AICD-57;
Short=AID(57); AltName: Full=Gamma-CTF(57); Contains: RecName: Full=Gamma-secretase
C-terminal fragment 50; AltName: Full=Amyloid intracellular domain 50; Short=AICD-50;
Short=AID(50); AltName: Full=Gamma-CTF(50); Contains: RecName: Full=C31; Flags:
Precursor;'
gene_info: Name=APP {ECO:0000312|HGNC:HGNC:620}; Synonyms=A4 {ECO:0000303|PubMed:2881207},
AD1 {ECO:0000312|HGNC:HGNC:620};
organism_full: Homo sapiens (Human).
protein_family: Belongs to the APP family. {ECO:0000255|PROSITE-
protein_domains: Amyloid_Cu-bd_sf. (IPR036669); Amyloid_glyco. (IPR008155); Amyloid_glyco_Abeta.
(IPR013803); Amyloid_glyco_Abeta_sf. (IPR037071); Amyloid_glyco_Cu-bd. (IPR011178)
provider_config:
timeout: 600
max_retries: 3
parameters:
allowed_domains: []
temperature: 0.1
citation_count: 35

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P05067
Protein Description: RecName: Full=Amyloid-beta precursor protein {ECO:0000312|HGNC:HGNC:620}; Short=APP {ECO:0000312|HGNC:HGNC:620}; AltName: Full=ABPP; AltName: Full=APPI; AltName: Full=Alzheimer disease amyloid A4 protein homolog; AltName: Full=Alzheimer disease amyloid protein; AltName: Full=Amyloid precursor protein {ECO:0000305}; AltName: Full=Amyloid-beta (A4) precursor protein {ECO:0000250|UniProtKB:P12023}; AltName: Full=Amyloid-beta A4 protein; AltName: Full=Cerebral vascular amyloid peptide; Short=CVAP; AltName: Full=PreA4; AltName: Full=Protease nexin-II; Short=PN-II; Contains: RecName: Full=N-APP; Contains: RecName: Full=Soluble APP-alpha {ECO:0000303|PubMed:10656250}; Short=S-APP-alpha {ECO:0000303|PubMed:10656250}; Contains: RecName: Full=Soluble APP-beta {ECO:0000303|PubMed:10656250}; Short=S-APP-beta {ECO:0000303|PubMed:10656250}; Contains: RecName: Full=C99; AltName: Full=Beta-secretase C-terminal fragment {ECO:0000303|PubMed:10656250}; Short=Beta-CTF {ECO:0000303|PubMed:10656250}; Contains: RecName: Full=Amyloid-beta protein 42 {ECO:0000303|PubMed:8886002}; Short=Abeta42; AltName: Full=Beta-APP42; Contains: RecName: Full=Amyloid-beta protein 40 {ECO:0000303|PubMed:8886002}; Short=Abeta40; AltName: Full=Beta-APP40; Contains: RecName: Full=C83; AltName: Full=Alpha-secretase C-terminal fragment {ECO:0000303|PubMed:10656250}; Short=Alpha-CTF {ECO:0000303|PubMed:10656250}; Contains: RecName: Full=P3(42); Contains: RecName: Full=P3(40); Contains: RecName: Full=C80; Contains: RecName: Full=Gamma-secretase C-terminal fragment 59; AltName: Full=Amyloid intracellular domain 59; Short=AICD-59; Short=AID(59); AltName: Full=Gamma-CTF(59); Contains: RecName: Full=Gamma-secretase C-terminal fragment 57; AltName: Full=Amyloid intracellular domain 57; Short=AICD-57; Short=AID(57); AltName: Full=Gamma-CTF(57); Contains: RecName: Full=Gamma-secretase C-terminal fragment 50; AltName: Full=Amyloid intracellular domain 50; Short=AICD-50; Short=AID(50); AltName: Full=Gamma-CTF(50); Contains: RecName: Full=C31; Flags: Precursor;
Gene Information: Name=APP {ECO:0000312|HGNC:HGNC:620}; Synonyms=A4 {ECO:0000303|PubMed:2881207}, AD1 {ECO:0000312|HGNC:HGNC:620};
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the APP family. {ECO:0000255|PROSITE-
Key Domains: Amyloid_Cu-bd_sf. (IPR036669); Amyloid_glyco. (IPR008155); Amyloid_glyco_Abeta. (IPR013803); Amyloid_glyco_Abeta_sf. (IPR037071); Amyloid_glyco_Cu-bd. (IPR011178)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "APP" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'APP' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene APP (gene ID: APP, UniProt: P05067) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P05067
Protein Description: RecName: Full=Amyloid-beta precursor protein {ECO:0000312|HGNC:HGNC:620}; Short=APP {ECO:0000312|HGNC:HGNC:620}; AltName: Full=ABPP; AltName: Full=APPI; AltName: Full=Alzheimer disease amyloid A4 protein homolog; AltName: Full=Alzheimer disease amyloid protein; AltName: Full=Amyloid precursor protein {ECO:0000305}; AltName: Full=Amyloid-beta (A4) precursor protein {ECO:0000250|UniProtKB:P12023}; AltName: Full=Amyloid-beta A4 protein; AltName: Full=Cerebral vascular amyloid peptide; Short=CVAP; AltName: Full=PreA4; AltName: Full=Protease nexin-II; Short=PN-II; Contains: RecName: Full=N-APP; Contains: RecName: Full=Soluble APP-alpha {ECO:0000303|PubMed:10656250}; Short=S-APP-alpha {ECO:0000303|PubMed:10656250}; Contains: RecName: Full=Soluble APP-beta {ECO:0000303|PubMed:10656250}; Short=S-APP-beta {ECO:0000303|PubMed:10656250}; Contains: RecName: Full=C99; AltName: Full=Beta-secretase C-terminal fragment {ECO:0000303|PubMed:10656250}; Short=Beta-CTF {ECO:0000303|PubMed:10656250}; Contains: RecName: Full=Amyloid-beta protein 42 {ECO:0000303|PubMed:8886002}; Short=Abeta42; AltName: Full=Beta-APP42; Contains: RecName: Full=Amyloid-beta protein 40 {ECO:0000303|PubMed:8886002}; Short=Abeta40; AltName: Full=Beta-APP40; Contains: RecName: Full=C83; AltName: Full=Alpha-secretase C-terminal fragment {ECO:0000303|PubMed:10656250}; Short=Alpha-CTF {ECO:0000303|PubMed:10656250}; Contains: RecName: Full=P3(42); Contains: RecName: Full=P3(40); Contains: RecName: Full=C80; Contains: RecName: Full=Gamma-secretase C-terminal fragment 59; AltName: Full=Amyloid intracellular domain 59; Short=AICD-59; Short=AID(59); AltName: Full=Gamma-CTF(59); Contains: RecName: Full=Gamma-secretase C-terminal fragment 57; AltName: Full=Amyloid intracellular domain 57; Short=AICD-57; Short=AID(57); AltName: Full=Gamma-CTF(57); Contains: RecName: Full=Gamma-secretase C-terminal fragment 50; AltName: Full=Amyloid intracellular domain 50; Short=AICD-50; Short=AID(50); AltName: Full=Gamma-CTF(50); Contains: RecName: Full=C31; Flags: Precursor;
Gene Information: Name=APP {ECO:0000312|HGNC:HGNC:620}; Synonyms=A4 {ECO:0000303|PubMed:2881207}, AD1 {ECO:0000312|HGNC:HGNC:620};
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the APP family. {ECO:0000255|PROSITE-
Key Domains: Amyloid_Cu-bd_sf. (IPR036669); Amyloid_glyco. (IPR008155); Amyloid_glyco_Abeta. (IPR013803); Amyloid_glyco_Abeta_sf. (IPR037071); Amyloid_glyco_Cu-bd. (IPR011178)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "APP" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene APP (gene ID: APP, UniProt: P05067) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Comprehensive Research Report: Human APP (Amyloid-beta Precursor Protein; UniProt P05067)

0. Target verification (critical disambiguation)

The UniProt accession P05067 corresponds to human amyloid-beta precursor protein (APP), a type I single-pass transmembrane glycoprotein with major brain isoform APP695 and additional KPI-containing isoforms (APP751/APP770). Multiple independent 2023–2024 sources explicitly describe this same human APP protein and its canonical secretase-dependent processing into sAPPα/sAPPβ, C83/C99, Aβ peptides, and AICD, matching the UniProt description and fragments list. (strope2024thereciprocalrelationship pages 3-4, masi2023thelabyrinthinelandscape pages 2-4, wang2024advancesinthe pages 2-4, martinezdrudis2024roleofpololike pages 32-36)

1. Key concepts & definitions (current understanding)

1.1 What APP is

APP is a type I transmembrane protein that undergoes extensive post-translational modification (e.g., glycosylation, phosphorylation) and is transported through the constitutive secretory system before surface delivery and endocytosis. (strope2024thereciprocalrelationship pages 3-4, martinezdrudis2024roleofpololike pages 32-36)

At the gene level, APP is located on chromosome 21 and is alternatively spliced into multiple isoforms, with APP695 predominant in neurons and longer isoforms (APP751/770) also present in non-neuronal cells. (strope2024thereciprocalrelationship pages 3-4, masi2023thelabyrinthinelandscape pages 2-4)

1.2 Canonical APP processing pathways

APP is proteolytically processed in two principal routes that are defined by the first cleavage event:

Non-amyloidogenic pathway (α → γ):
- α-secretase (often ADAM10) cleaves APP to release sAPPα and leave a membrane C-terminal fragment C83 (CTFα).
- γ-secretase then cleaves C83 to generate p3 and the APP intracellular domain (AICD). (strope2024thereciprocalrelationship pages 3-4, baron2024regulationofamyloid pages 41-44, wang2024advancesinthe pages 2-4)

Amyloidogenic pathway (β → γ):
- β-secretase (BACE1) cleaves APP to release sAPPβ and leave C99 (CTFβ).
- γ-secretase cleaves C99 to release Aβ peptides (that can oligomerize and deposit) and AICD. (strope2024thereciprocalrelationship pages 3-4, baron2024regulationofamyloid pages 41-44, wang2024advancesinthe pages 2-4)

A schematic summary of these pathways and products is shown in a recent cell-biology review figure. (wang2024advancesinthe media 1a611bbf)

1.3 Enzymology focus (substrates, specificity)

APP itself is not an enzyme; it is a substrate for multiple proteases. In functional-annotation terms, APP’s “primary biochemical function” in AD biology is best described as: a membrane protein whose regulated proteolysis produces bioactive extracellular and intracellular fragments, including Aβ species and signaling-competent AICD. (strope2024thereciprocalrelationship pages 3-4, wang2024advancesinthe pages 2-4)

2. Subcellular localization, trafficking, and where processing occurs

2.1 Trafficking route and compartmentalization

A current model emphasizes trafficking-driven regulation of APP processing:
- APP is synthesized in the ER, matures in the Golgi/TGN, and traffics to the plasma membrane, where only a minority of newly made APP appears (~10% at the surface in one reviewed estimate). (strope2024thereciprocalrelationship pages 3-4)
- APP undergoes rapid endocytosis into endosomes and is either recycled or directed to lysosomal degradation. (strope2024thereciprocalrelationship pages 3-4, masi2023thelabyrinthinelandscape pages 2-4)

2.2 Why localization matters for Aβ generation

Processing is spatially segregated:
- α-secretase cleavage is highlighted as occurring mainly at the plasma membrane.
- β-secretase (BACE1) is enriched in acidic endosomal/lysosomal compartments, making endocytosis and endosome residency key determinants of amyloidogenic processing. (strope2024thereciprocalrelationship pages 3-4, masi2023thelabyrinthinelandscape pages 2-4, martinezdrudis2024roleofpololike pages 32-36)

More recent cell-biology work also emphasizes that co-localization of APP and secretases in the same membrane sub-compartment is required for cleavage and that advanced imaging (including super-resolution approaches) is refining understanding of where APP and BACE1 co-reside. (wang2024advancesinthe pages 2-4, wang2024advancesinthe pages 1-2)

3. Physiological functions of APP and major biological processes

APP and its fragments are implicated in multiple physiological processes, particularly in neurons and synapses:

3.1 Synaptic development and function

APP is described as highly expressed at synapses and implicated in synaptic development and function, with knockout models showing synaptic and behavioral deficits, supporting an endogenous physiological role beyond pathology. (strope2024thereciprocalrelationship pages 3-4)

3.2 Adhesion- and receptor-like functions

Reviews highlight APP’s receptor-like and adhesion-associated roles, including motifs associated with cell adhesion and neurodevelopmental processes (synaptogenesis, neurite outgrowth). (strope2024thereciprocalrelationship pages 3-4, masi2023thelabyrinthinelandscape pages 11-13, baron2024regulationofamyloid pages 41-44)

3.3 Trophic activity of soluble APP fragments

The extracellular soluble fragment sAPPα is repeatedly described as neurotrophic/neuroprotective and often contrasted with sAPPβ as having stronger trophic effects. (masi2023thelabyrinthinelandscape pages 11-13, baron2024regulationofamyloid pages 41-44, masi2023thelabyrinthinelandscape pages 29-30)

3.4 Mitochondria- and bioenergetics-linked biology

A 2024 review stresses that APP, secretases, and APP processing products localize to multiple organelles (including endosomes, ER, mitochondria, and ER–mitochondria contact sites) and argues that relationships between APP metabolism and mitochondrial function remain incompletely resolved but are increasingly studied as part of AD-relevant cell physiology. (strope2024thereciprocalrelationship pages 3-4)

4. Recent developments (prioritizing 2023–2024)

4.1 “APP dyshomeostasis” framing beyond Aβ alone

A 2024 review argues that AD may reflect “APP dyshomeostasis” in which Aβ is important but not the only relevant output, emphasizing that APP dysfunction may impact multiple APP-mediated functions (signaling, synaptic plasticity, adhesion) and that therapeutic strategies beyond anti-Aβ remain underdeveloped. (sirisi2024appdyshomeostasisin pages 1-2)

4.2 Trafficking as a mechanistic bottleneck

The 2024 Biochemical Journal review emphasizes that intracellular trafficking of APP and BACE1 is critical for regulating amyloidogenic processing and Aβ production and that familial AD mutations can impact these trafficking/processing relationships. (wang2024advancesinthe pages 1-2, wang2024advancesinthe pages 2-4)

4.3 Precision targeting of γ-secretase: modulation/stabilization vs inhibition

Two 2024 expert perspectives synthesize why early γ-secretase inhibitors failed clinically (notably via Notch-related toxicities due to γ-secretase’s many substrates), and argue for a precision approach:
- De Strooper & Karran propose γ-secretase allosteric stabilizers (GSAS) that increase processivity and shift the Aβ length distribution away from longer aggregation-prone peptides, conceptually opposite to effects of pathogenic presenilin mutations. (strooper2024newprecisionmedicine pages 1-2, strooper2024newprecisionmedicine pages 2-3)
- Wolfe highlights additional complexity: familial AD mutations may cause altered trimming dynamics or potentially harmful stabilization of stalled enzyme–substrate complexes, motivating careful design of modulators rather than broad inhibition. (wolfe2024γsecretaseonceand pages 3-4, wolfe2024γsecretaseonceand pages 1-3)

4.4 TBI and APP: convergence of injury biology and amyloidogenesis

A 2023 synthesis highlights that traumatic brain injury can increase expression of APP and amyloidogenic cleavage enzymes near injured axons, linking APP metabolism to post-injury neurodegenerative risk and emphasizing roles of fragments (e.g., sAPPα neuroprotection vs β-CTF/N-APP synaptotoxicity) and inflammatory signaling pathways. (masi2023thelabyrinthinelandscape pages 11-13, masi2023thelabyrinthinelandscape pages 29-30)

5. Current applications and real-world implementations

5.1 Blood-based biomarkers reflecting APP/Aβ brain pathology (2024)

Although APP is not typically measured directly in blood for clinical decision-making, APP-derived Aβ peptides (especially the Aβ42/40 ratio) are key components of plasma biomarker panels that aim to infer brain amyloid status (PET/CSF).

(A) Trial-ready screening use (J-TRC and BioFINDER)

Niimi et al. (May 2024; Alzheimer’s Research & Therapy) evaluated plasma biomarkers against Aβ-PET in J-TRC (n=474) and BioFINDER (n=177). Peak AUCs for detecting abnormal Aβ-PET reached 0.936–0.955 in J-TRC using models combining plasma Aβ measures and p-tau217 plus basic covariates (age/sex/APOE), with replication AUCs 0.914–0.938 in BioFINDER. (niimi2024combiningplasmaaβ pages 1-2)

URL: https://doi.org/10.1186/s13195-024-01469-w (May 2024). (niimi2024combiningplasmaaβ pages 1-2)

(B) Memory-clinic implementation potential

Dyer et al. (Aug 2024; Alzheimer’s Research & Therapy) evaluated p-tau217 in a memory-clinic cohort (n=108, 64.8% Aβ+ by CSF). Plasma p-tau217 was >3-fold higher in Aβ+ vs Aβ− (median 12.4 pg/mL vs 3.7 pg/mL) and achieved AUC 0.91 for detecting Aβ pathology. A two-threshold strategy could avoid 58–68% of lumbar punctures in this setting (model-based estimate). (dyer2024performanceofplasma pages 1-2)

URL: https://doi.org/10.1186/s13195-024-01555-z (Aug 2024). (dyer2024performanceofplasma pages 1-2)

(C) Commercial test validation: PrecivityAD2 (mass spectrometry)

Meyer et al. (Mar 2024; Alzheimer’s & Dementia) validated a high-throughput LC-MS/MS blood test combining %p-tau217 with Aβ42/40 (PrecivityAD2 / APS2) in n=583 suspected-AD individuals (53% PET-positive). At APS2 cut point 47.5, sensitivity was 88% (95% CI 84–91%) and specificity 89% (95% CI 84–92%), with ~88% agreement vs amyloid PET. Extremes of APS2 (>80 or <20) covered 69% of the cohort and achieved ≥95% combined accuracy, while an intermediate category (9.6%) had PPV 92% and NPV 91% at observed prevalence 53.6%. (meyer2024clinicalvalidationof pages 10-12)

URL: https://doi.org/10.1002/alz.13764 (Mar 2024). (meyer2024clinicalvalidationof pages 1-2, meyer2024clinicalvalidationof pages 10-12)

5.2 Therapeutics that act downstream of APP: anti-Aβ monoclonal antibodies

Anti-Aβ antibodies do not target APP directly but operate on the downstream products of APP cleavage. Recent trial/implementation evidence reinforces the translational centrality of APP proteolysis.

Donanemab (TRAILBLAZER-ALZ 2; subpopulation analysis)

Sato et al. (Apr 2024; Neurology and Therapy) report that in Japanese participants (N=88) of TRAILBLAZER-ALZ 2, donanemab showed 38.8–40.2% slowing of progression on iADRS vs placebo (week 76). Amyloid plaque clearance to <24.1 Centiloids occurred in 83.3% of donanemab-treated participants vs 0% placebo. ARIA-E occurred in 22.2% of donanemab-treated vs 2.3% placebo, with 2.2% symptomatic in donanemab-treated. (sato2024donanemabinjapanese pages 1-2)

URL: https://doi.org/10.1007/s40120-024-00604-x (Apr 2024). (sato2024donanemabinjapanese pages 1-2)

Plaque reduction vs clinical benefit (cross-program synthesis)

A 2024 synthesis argues that across late-phase anti-Aβ IgG programs, greater plaque reduction (using SUVR/centiloid harmonization) associates with better preservation of clinical function on placebo-adjusted CDR-SB. (lian2024clarityonthe pages 29-33)

URL: https://doi.org/10.1038/s41380-023-02324-4 (published 2024 issue; Molecular Psychiatry). (lian2024clarityonthe pages 29-33)

6. Expert opinions and analysis (authoritative perspectives)

6.1 Consensus and controversy: amyloid hypothesis and what it implies for APP

Expert reviews emphasize that genetics (APP and presenilin mutations) strongly tie AD to APP processing and Aβ generation, yet clinical translation is complicated: anti-Aβ antibodies show modest cognitive slowing and carry safety risks (ARIA), and amyloid burden correlates imperfectly with cognition and mismatches tau topography, suggesting APP dyshomeostasis affects multiple dimensions of neuronal function. (sirisi2024appdyshomeostasisin pages 1-2, wolfe2024γsecretaseonceand pages 1-3)

6.2 Where the field is heading

Two convergent 2024 perspectives propose that success may require (i) earlier intervention and (ii) more precise control of γ-secretase processivity, avoiding broad inhibition that disrupts Notch and other substrates. De Strooper & Karran’s GSAS framing explicitly defines a next-generation mechanism-based prevention concept. (strooper2024newprecisionmedicine pages 1-2, strooper2024newprecisionmedicine pages 2-3)

7. Key statistics & data (selected highlights)

7.1 Biomarker performance (plasma, 2024)

J-TRC/BioFINDER detection of Aβ-PET positivity: AUC up to 0.955 (J-TRC) and replicated AUC up to 0.938 (BioFINDER) using combined plasma biomarkers and covariates. (niimi2024combiningplasmaaβ pages 1-2)
PrecivityAD2 (APS2) vs PET: sensitivity 88%, specificity 89%, PPV 92% and NPV 91% (intermediate category; prevalence 53.6%). (meyer2024clinicalvalidationof pages 10-12)
Memory-clinic p-tau217: AUC 0.91; p-tau217 ~12.4 pg/mL (Aβ+) vs 3.7 pg/mL (Aβ−). (dyer2024performanceofplasma pages 1-2)
Preclinical PET classification improvements (AHEAD, 2024): Aβ42/40 alone AUC 0.87, p-tau217/np-tau217 ratio AUC 0.92, combined model AUC 0.95. (rissman2024plasmaaβ42aβ40and pages 1-2)

7.2 Therapeutic outcomes (anti-Aβ, 2024)

Donanemab (TRAILBLAZER-ALZ 2 Japan subpopulation): iADRS slowing 38.8–40.2%; amyloid clearance 83.3% vs 0%; ARIA-E 22.2% vs 2.3%. (sato2024donanemabinjapanese pages 1-2)

8. Evidence-supported functional annotation summary (for databases)

Molecular function (annotation-style): Type I transmembrane protein and protease substrate whose regulated proteolysis generates soluble ectodomains (sAPPα/sAPPβ), membrane CTFs (C83/C99), Aβ peptides, and AICD; fragment signaling and trafficking-dependent cleavage underpin both physiological synaptic functions and AD-related pathology. (strope2024thereciprocalrelationship pages 3-4, wang2024advancesinthe pages 2-4, wang2024advancesinthe media 1a611bbf)

Biological processes: Secretory trafficking and endocytosis; synapse development and plasticity; cell adhesion; production of amyloidogenic peptides via BACE1/γ-secretase; modulation of neuronal homeostasis and mitochondrial-linked physiology (area of active research). (strope2024thereciprocalrelationship pages 3-4, wang2024advancesinthe pages 2-4)

Cellular components (where it acts): ER/Golgi/TGN (biosynthesis and sorting), plasma membrane (surface residence and α-cleavage), endosomes/endo-lysosomal system (β-cleavage and sorting), with reported localization of APP and metabolites also in mitochondria and ER–mitochondria contacts in reviewed literature. (strope2024thereciprocalrelationship pages 3-4, masi2023thelabyrinthinelandscape pages 2-4)

Summary Table

Aspect	Current Understanding (2023–2024)	Key Quantitative Data	Key Sources
Protein Identity & Structure	Human APP (P05067) is a Type I transmembrane protein. Major neuronal isoform is APP695; others (APP751/770) contain KPI domains. Includes E1/E2 extracellular domains and a C-terminal internalization motif (YENPTY).	Gene: APP on Chr 21, ~400kbp, 18 exons. p3 fragment size ~3 kDa.	Strope & Wilkins, 2024 (strope2024thereciprocalrelationship pages 3-4); Masi et al., 2023 (masi2023thelabyrinthinelandscape pages 2-4); Martínez-Drudis, 2024 (martinezdrudis2024roleofpololike pages 32-36)
Processing Pathways	Non-amyloidogenic: $\alpha$-secretase (ADAM10) $\to$ sAPP$\alpha$ + C83. Amyloidogenic: $\beta$-secretase (BACE1) $\to$ sAPP$\beta$ + C99 $\to$ A$\beta$. $\gamma$-secretase cleavage generates AICD. "Allosteric stabilizers" (GSAS) proposed to fix processivity rather than inhibit enzyme.	Cleavage products: sAPP$\alpha$, sAPP$\beta$, C83, C99, A$\beta$, AICD.	Wang et al., 2024 (wang2024advancesinthe pages 2-4); De Strooper & Karran, 2024 (strooper2024newprecisionmedicine pages 1-2); Figure 1 (wang2024advancesinthe media 1a611bbf)
Trafficking & Localization	Traffics via secretory pathway (ER $\to$ Golgi $\to$ PM) and endocytic routes. Processing is spatially regulated: $\alpha$-cleavage mainly at PM; $\beta$-cleavage in acidic endosomes.	~10% of nascent APP reaches cell surface. Super-resolution reveals low APP-BACE1 co-localization in secretory organelles.	Strope & Wilkins, 2024 (strope2024thereciprocalrelationship pages 3-4); Wang et al., 2024 (wang2024advancesinthe pages 2-4); Baron, 2024 (baron2024regulationofamyloid pages 41-44)
Physiological Functions	Synaptic formation, plasticity, and cell adhesion (synaptic adhesion molecule). sAPP$\alpha$ is neurotrophic/neuroprotective. Modulates mitochondrial function and bioenergetics.	-	Strope & Wilkins, 2024 (strope2024thereciprocalrelationship pages 3-4); Masi et al., 2023 (masi2023thelabyrinthinelandscape pages 29-30); Baron, 2024 (baron2024regulationofamyloid pages 41-44)
Disease Relevance (AD)	FAD mutations destabilize $\gamma$-secretase/substrate, increasing toxic long A$\beta$. APP/CTF accumulation at organelle contacts disrupts lysosomes. TBI upregulates APP/secretases.	Presenilin mutations affect A$\beta$ length spectrum.	De Strooper & Karran, 2024 (strooper2024newprecisionmedicine pages 1-2); Wang et al., 2024 (wang2024advancesinthe pages 2-4); Masi et al., 2023 (masi2023thelabyrinthinelandscape pages 11-13)
Clinical Biomarkers	Plasma p-tau217 and A$\beta$42/40 ratio accurately predict brain amyloid status (PET), reducing need for invasive tests. Used in "PrecivityAD2" and trials.	AUC 0.94–0.96 for p-tau217/A$\beta$42 models; 88% Sensitivity / 89% Specificity for PrecivityAD2 vs PET.	Niimi et al., 2024 (niimi2024combiningplasmaaβ pages 1-2); Meyer et al., 2024 (meyer2024clinicalvalidationof pages 1-2); Dyer et al., 2024 (dyer2024performanceofplasma pages 1-2)
Therapeutic Targeting	Anti-amyloid mAbs (Lecanemab, Donanemab) remove plaques and slow cognitive decline. Focus shifting from broad $\gamma$-secretase inhibitors to modulators/stabilizers (GSAS).	Donanemab slowed decline by ~38–40% (iADRS) in early AD; 83.3% of treated Japanese sub-cohort achieved clearance (<24.1 Centiloids).	Sato et al., 2024 (sato2024donanemabinjapanese pages 1-2); Ribeiro et al., 2024 (ribeiro2024therapeuticanalysisof pages 18-21); De Strooper & Karran, 2024 (strooper2024newprecisionmedicine pages 1-2)

Table: This table synthesizes current research (2023–2024) on the structure, processing, biological roles, and clinical applications associated with human APP, highlighting quantitative biomarker performance and therapeutic outcomes.

Key mechanistic figure (APP processing)

A figure depicting the non-amyloidogenic and amyloidogenic processing of APP (secretases and fragment products) is available from the Biochemical Journal 2024 review. (wang2024advancesinthe media 1a611bbf)

References

(strope2024thereciprocalrelationship pages 3-4): Taylor A. Strope and Heather M. Wilkins. The reciprocal relationship between amyloid precursor protein and mitochondrial function. Journal of Neurochemistry, 168:2275-2284, Jul 2024. URL: https://doi.org/10.1111/jnc.16183, doi:10.1111/jnc.16183. This article has 9 citations and is from a domain leading peer-reviewed journal.
(masi2023thelabyrinthinelandscape pages 2-4): Mirco Masi, Fabrizio Biundo, André Fiou, Marco Racchi, Alessia Pascale, and Erica Buoso. The labyrinthine landscape of app processing: state of the art and possible novel soluble app-related molecular players in traumatic brain injury and neurodegeneration. International Journal of Molecular Sciences, 24:6639, Apr 2023. URL: https://doi.org/10.3390/ijms24076639, doi:10.3390/ijms24076639. This article has 20 citations.
(wang2024advancesinthe pages 2-4): Jingqi Wang, Lou Fourriere, and Paul A. Gleeson. Advances in the cell biology of the trafficking and processing of amyloid precursor protein: impact of familial alzheimer's disease mutations. Biochemical Journal, 481:1297-1325, Sep 2024. URL: https://doi.org/10.1042/bcj20240056, doi:10.1042/bcj20240056. This article has 15 citations and is from a domain leading peer-reviewed journal.
(martinezdrudis2024roleofpololike pages 32-36): L Martínez-Drudis. Role of polo-like kinase 2 in the pathogenesis and treatment of alzheimer's disease. Unknown journal, 2024.
(baron2024regulationofamyloid pages 41-44): SKV Baron. Regulation of amyloid precursor protein processing pathway by β-secretase and its impact on alzheimer's disease physiopathology. Unknown journal, 2024.
(wang2024advancesinthe media 1a611bbf): Jingqi Wang, Lou Fourriere, and Paul A. Gleeson. Advances in the cell biology of the trafficking and processing of amyloid precursor protein: impact of familial alzheimer's disease mutations. Biochemical Journal, 481:1297-1325, Sep 2024. URL: https://doi.org/10.1042/bcj20240056, doi:10.1042/bcj20240056. This article has 15 citations and is from a domain leading peer-reviewed journal.
(wang2024advancesinthe pages 1-2): Jingqi Wang, Lou Fourriere, and Paul A. Gleeson. Advances in the cell biology of the trafficking and processing of amyloid precursor protein: impact of familial alzheimer's disease mutations. Biochemical Journal, 481:1297-1325, Sep 2024. URL: https://doi.org/10.1042/bcj20240056, doi:10.1042/bcj20240056. This article has 15 citations and is from a domain leading peer-reviewed journal.
(masi2023thelabyrinthinelandscape pages 11-13): Mirco Masi, Fabrizio Biundo, André Fiou, Marco Racchi, Alessia Pascale, and Erica Buoso. The labyrinthine landscape of app processing: state of the art and possible novel soluble app-related molecular players in traumatic brain injury and neurodegeneration. International Journal of Molecular Sciences, 24:6639, Apr 2023. URL: https://doi.org/10.3390/ijms24076639, doi:10.3390/ijms24076639. This article has 20 citations.
(masi2023thelabyrinthinelandscape pages 29-30): Mirco Masi, Fabrizio Biundo, André Fiou, Marco Racchi, Alessia Pascale, and Erica Buoso. The labyrinthine landscape of app processing: state of the art and possible novel soluble app-related molecular players in traumatic brain injury and neurodegeneration. International Journal of Molecular Sciences, 24:6639, Apr 2023. URL: https://doi.org/10.3390/ijms24076639, doi:10.3390/ijms24076639. This article has 20 citations.
(sirisi2024appdyshomeostasisin pages 1-2): Sònia Sirisi, Érika Sánchez-Aced, Olivia Belbin, and Alberto Lleó. App dyshomeostasis in the pathogenesis of alzheimer’s disease: implications for current drug targets. Alzheimer's Research & Therapy, Jun 2024. URL: https://doi.org/10.1186/s13195-024-01504-w, doi:10.1186/s13195-024-01504-w. This article has 30 citations and is from a domain leading peer-reviewed journal.
(strooper2024newprecisionmedicine pages 1-2): Bart de Strooper and Eric H. Karran. New precision medicine avenues to the prevention of alzheimer’s disease from insights into the structure and function of γ-secretases. The EMBO Journal, 43(6):887-903, Feb 2024. URL: https://doi.org/10.1038/s44318-024-00057-w, doi:10.1038/s44318-024-00057-w. This article has 33 citations.
(strooper2024newprecisionmedicine pages 2-3): Bart de Strooper and Eric H. Karran. New precision medicine avenues to the prevention of alzheimer’s disease from insights into the structure and function of γ-secretases. The EMBO Journal, 43(6):887-903, Feb 2024. URL: https://doi.org/10.1038/s44318-024-00057-w, doi:10.1038/s44318-024-00057-w. This article has 33 citations.
(wolfe2024γsecretaseonceand pages 3-4): Michael S. Wolfe. Γ-secretase: once and future drug target for alzheimer’s disease. Expert Opinion on Drug Discovery, 19:5-8, Nov 2024. URL: https://doi.org/10.1080/17460441.2023.2277350, doi:10.1080/17460441.2023.2277350. This article has 15 citations and is from a peer-reviewed journal.
(wolfe2024γsecretaseonceand pages 1-3): Michael S. Wolfe. Γ-secretase: once and future drug target for alzheimer’s disease. Expert Opinion on Drug Discovery, 19:5-8, Nov 2024. URL: https://doi.org/10.1080/17460441.2023.2277350, doi:10.1080/17460441.2023.2277350. This article has 15 citations and is from a peer-reviewed journal.
(niimi2024combiningplasmaaβ pages 1-2): Yoshiki Niimi, Shorena Janelidze, Kenichiro Sato, Naoki Tomita, Tadashi Tsukamoto, Takashi Kato, Kenji Yoshiyama, Hisatomo Kowa, Atsushi Iwata, Ryoko Ihara, Kazushi Suzuki, Kensaku Kasuga, Takeshi Ikeuchi, Kenji Ishii, Kengo Ito, Akinori Nakamura, Michio Senda, Theresa A. Day, Samantha C. Burnham, Leonardo Iaccarino, Michael J. Pontecorvo, Oskar Hansson, and Takeshi Iwatsubo. Combining plasma aβ and p-tau217 improves detection of brain amyloid in non-demented elderly. Alzheimer's Research & Therapy, May 2024. URL: https://doi.org/10.1186/s13195-024-01469-w, doi:10.1186/s13195-024-01469-w. This article has 61 citations and is from a domain leading peer-reviewed journal.
(dyer2024performanceofplasma pages 1-2): Adam H. Dyer, Helena Dolphin, Antoinette O’Connor, Laura Morrison, Gavin Sedgwick, Conor Young, Emily Killeen, Conal Gallagher, Aoife McFeely, Eimear Connolly, Naomi Davey, Paul Claffey, Paddy Doyle, Shane Lyons, Christine Gaffney, Ruth Ennis, Cathy McHale, Jasmine Joseph, Graham Knight, Emmet Kelly, Cliona O’Farrelly, Aoife Fallon, Sean O’Dowd, Nollaig M. Bourke, and Sean P. Kennelly. Performance of plasma p-tau217 for the detection of amyloid-β positivity in a memory clinic cohort using an electrochemiluminescence immunoassay. Alzheimer's Research & Therapy, Aug 2024. URL: https://doi.org/10.1186/s13195-024-01555-z, doi:10.1186/s13195-024-01555-z. This article has 27 citations and is from a domain leading peer-reviewed journal.
(meyer2024clinicalvalidationof pages 10-12): Matthew R. Meyer, Kristopher M. Kirmess, Stephanie Eastwood, Traci L. Wente‐Roth, Faith Irvin, Mary S. Holubasch, Venky Venkatesh, Ilana Fogelman, Mark Monane, Lucy Hanna, Gil D. Rabinovici, Barry A. Siegel, Rachel A. Whitmer, Charles Apgar, Randall J. Bateman, David M. Holtzman, Michael Irizarry, David Verbel, Pallavi Sachdev, Satoshi Ito, John Contois, Kevin E. Yarasheski, Joel B. Braunstein, Philip B. Verghese, and Tim West. Clinical validation of the precivityad2 blood test: a mass spectrometry‐based test with algorithm combining %p‐tau217 and aβ42/40 ratio to identify presence of brain amyloid. Alzheimer's & Dementia, 20:3179-3192, Mar 2024. URL: https://doi.org/10.1002/alz.13764, doi:10.1002/alz.13764. This article has 105 citations and is from a highest quality peer-reviewed journal.
(meyer2024clinicalvalidationof pages 1-2): Matthew R. Meyer, Kristopher M. Kirmess, Stephanie Eastwood, Traci L. Wente‐Roth, Faith Irvin, Mary S. Holubasch, Venky Venkatesh, Ilana Fogelman, Mark Monane, Lucy Hanna, Gil D. Rabinovici, Barry A. Siegel, Rachel A. Whitmer, Charles Apgar, Randall J. Bateman, David M. Holtzman, Michael Irizarry, David Verbel, Pallavi Sachdev, Satoshi Ito, John Contois, Kevin E. Yarasheski, Joel B. Braunstein, Philip B. Verghese, and Tim West. Clinical validation of the precivityad2 blood test: a mass spectrometry‐based test with algorithm combining %p‐tau217 and aβ42/40 ratio to identify presence of brain amyloid. Alzheimer's & Dementia, 20:3179-3192, Mar 2024. URL: https://doi.org/10.1002/alz.13764, doi:10.1002/alz.13764. This article has 105 citations and is from a highest quality peer-reviewed journal.
(sato2024donanemabinjapanese pages 1-2): Shoichiro Sato, Naohisa Hatakeyama, Shinji Fujikoshi, Sadao Katayama, Hideaki Katagiri, and John R. Sims. Donanemab in japanese patients with early alzheimer’s disease: subpopulation analysis of the trailblazer-alz 2 randomized trial. Neurology and Therapy, 13:677-695, Apr 2024. URL: https://doi.org/10.1007/s40120-024-00604-x, doi:10.1007/s40120-024-00604-x. This article has 18 citations and is from a domain leading peer-reviewed journal.
(lian2024clarityonthe pages 29-33): Yan Lian, Yu-Juan Jia, Joelyn Wong, Xin-Fu Zhou, Weihong Song, Junhong Guo, Colin L. Masters, and Yan-Jiang Wang. Clarity on the blazing trail: clearing the way for amyloid-removing therapies for alzheimer’s disease. Molecular Psychiatry, 29(2):297-305, Nov 2024. URL: https://doi.org/10.1038/s41380-023-02324-4, doi:10.1038/s41380-023-02324-4. This article has 23 citations and is from a highest quality peer-reviewed journal.
(rissman2024plasmaaβ42aβ40and pages 1-2): Robert A. Rissman, Oliver Langford, Rema Raman, Michael C. Donohue, Sara Abdel‐Latif, Matthew R. Meyer, Traci Wente‐Roth, Kristopher M. Kirmess, Jennifer Ngolab, Charisse N. Winston, Gustavo Jimenez‐Maggiora, Michael S. Rafii, Pallavi Sachdev, Tim West, Kevin E. Yarasheski, Joel B. Braunstein, Michael Irizarry, Keith A. Johnson, Paul S. Aisen, and Reisa A. Sperling. Plasma aβ42/aβ40 and phospho‐tau217 concentration ratios increase the accuracy of amyloid pet classification in preclinical alzheimer's disease. Alzheimer's & Dementia, 20:1214-1224, Nov 2024. URL: https://doi.org/10.1002/alz.13542, doi:10.1002/alz.13542. This article has 130 citations and is from a highest quality peer-reviewed journal.
(ribeiro2024therapeuticanalysisof pages 18-21): Gabriel França Ribeiro, Isabella Gaiarim de Andrade, Marcos Augusto Bustamante de Vasconcellos, Rayanne Cruz Rodrigues, Márcia Bandeira Bringel, Geovanna Cristina Gonçalves da Silva Cordeiro, Gabriel Abrantes Farias, Sandra Inês Lins de Abreu Mendes, Ana Carolina Barambo Wagner, Juliana Nunes Ferreira Nascimento, Dieckson de Oliveira Batista, Gabriele Luisa de Souza Cruz, Stephany Fernandes de Paiva, Thainara Ferreira Campos, and Thaise Freire Andrade. Therapeutic analysis of donanemab in the treatment of patients with alzheimer's disease. Caderno Pedagógico, 21:e7019, Aug 2024. URL: https://doi.org/10.54033/cadpedv21n8-207, doi:10.54033/cadpedv21n8-207. This article has 0 citations.

Citations

strope2024thereciprocalrelationship pages 3-4
sirisi2024appdyshomeostasisin pages 1-2
dyer2024performanceofplasma pages 1-2
meyer2024clinicalvalidationof pages 10-12
sato2024donanemabinjapanese pages 1-2
lian2024clarityonthe pages 29-33
masi2023thelabyrinthinelandscape pages 2-4
martinezdrudis2024roleofpololike pages 32-36
wang2024advancesinthe pages 2-4
strooper2024newprecisionmedicine pages 1-2
baron2024regulationofamyloid pages 41-44
masi2023thelabyrinthinelandscape pages 29-30
masi2023thelabyrinthinelandscape pages 11-13
meyer2024clinicalvalidationof pages 1-2
ribeiro2024therapeuticanalysisof pages 18-21
wang2024advancesinthe pages 1-2
strooper2024newprecisionmedicine pages 2-3
https://doi.org/10.1186/s13195-024-01469-w
https://doi.org/10.1186/s13195-024-01555-z
https://doi.org/10.1002/alz.13764
https://doi.org/10.1007/s40120-024-00604-x
https://doi.org/10.1038/s41380-023-02324-4
https://doi.org/10.1111/jnc.16183,
https://doi.org/10.3390/ijms24076639,
https://doi.org/10.1042/bcj20240056,
https://doi.org/10.1186/s13195-024-01504-w,
https://doi.org/10.1038/s44318-024-00057-w,
https://doi.org/10.1080/17460441.2023.2277350,
https://doi.org/10.1186/s13195-024-01469-w,
https://doi.org/10.1186/s13195-024-01555-z,
https://doi.org/10.1002/alz.13764,
https://doi.org/10.1007/s40120-024-00604-x,
https://doi.org/10.1038/s41380-023-02324-4,
https://doi.org/10.1002/alz.13542,
https://doi.org/10.54033/cadpedv21n8-207,

Notes

(APP-notes.md)

APP - Amyloid Precursor Protein (Human) Notes

Overview

Human APP (P05067) is the ortholog of mouse App. The biology is essentially identical - a type I transmembrane protein that undergoes regulated intramembrane proteolysis (RIP) to produce multiple bioactive fragments.

Key difference from mouse: Human APP is directly relevant to Alzheimer's disease pathology. The human Abeta sequence differs slightly from mouse, and human Abeta is more prone to aggregation. AD mouse models often use humanized APP.

Splice Isoforms

Isoform	UniProt	Length	Domains	Expression
APP770	P05067-1	770 AA	KPI + OX-2	Peripheral, microglia
APP751	P05067-6	751 AA	KPI only	Peripheral tissues
APP695	P05067-4	695 AA	No KPI	Neuronal (predominant in brain)
L-APP677	P05067-3	677 AA	No KPI	Leukocytes
APP305	P05067-2	305 AA	Truncated	Limited data

Cleavage Products

Same as mouse - see mouse App notes for details:
- sAPPalpha (neuroprotective)
- sAPPbeta (less neurotrophic, DR6 binding)
- Abeta40/42 (neurotoxic, AD pathogenic)
- AICD (nuclear signaling)
- N-APP (axon pruning via DR6)

Familial AD Mutations

Human APP mutations cause familial Alzheimer's disease by increasing Abeta42/Abeta40 ratio:

Mutation	Position	Effect
Swedish	K670N/M671L	Increases total Abeta
London	V717I	Increases Abeta42/40 ratio
Flemish	A692G	Increases Abeta aggregation
Arctic	E693G	Increases protofibril formation
Iowa	D694N	Increases cerebral amyloid angiopathy

Key Human-Specific Points

Human Abeta sequence at positions 5, 10, 13 differs from rodent - more aggregation-prone
Most AD mouse models use human APP transgenes
Down syndrome (trisomy 21) causes AD due to APP gene triplication on chromosome 21
Protective mutation (A673T, "Icelandic") reduces Abeta production and AD risk

References

PMID:2881207 - Original APP cloning
PMID:8886002 - Swedish mutation characterization
PMID:23150908 - Icelandic protective mutation

Bioreason Rl Review

(APP-bioreason-rl-review.md)

BioReason-Pro RL Review: APP (human)

Source: APP-deep-research-bioreason-rl.md

Correctness: 4/5
Completeness: 4/5

Functional Summary Review

The BioReason functional summary describes APP as:

A single-pass membrane glycoprotein that assembles a large extracellular platform for glycosaminoglycan engagement and regulated proteolysis, coupled to a cytosolic tail that recruits trafficking and signaling adaptors. Its ectodomain binds heparin and coordinates copper to stabilize matrix interactions, while a built-in Kunitz module modulates pericellular protease activity and an E2 repeat supports folding and shedding. Sequential cleavage events yield soluble ectodomains and amyloidogenic peptides, linking extracellular adhesion to intracellular signaling.

This is a strong summary that correctly identifies most of APP's key structural and functional features. The description of the heparin-binding domain, copper-binding domain, Kunitz protease inhibitor domain, and E2 domain is accurate and well-grounded in InterPro architecture. The mention of "sequential cleavage events" yielding "amyloidogenic peptides" correctly captures the biology of amyloid-beta generation.

The curated review describes APP as a type I transmembrane protein with roles in neurite outgrowth (GO:0031175), serine-type endopeptidase inhibitor activity (GO:0004867), cell adhesion, signaling receptor activity, and endocytosis. BioReason captures the protease inhibitor function via the Kunitz domain, the cell adhesion aspects via heparin binding, and endocytic routing via the cytosolic tail. One minor gap: BioReason does not explicitly mention APP's role as a signaling receptor or its involvement in neurite outgrowth and neuronal biology, which the curated review highlights. The Notch signaling pathway annotation (GO:0007219) was REMOVED in the curated review, and BioReason correctly does not invoke it.

The description of the cytosolic PH-like fold is reasonable but slightly over-interpreted -- the AICD (APP intracellular domain) functions more as a transcriptional regulator and adaptor-binding platform than a classical PH domain.

Comparison with interpro2go:

The curated review includes an interpro2go (GO_REF:0000002) annotation for transition metal ion binding (GO:0046914), which was accepted. BioReason correctly identifies copper binding from IPR011178/IPR036669. The interpro2go pipeline maps these domains to metal ion binding terms, and BioReason recapitulates the same logic but adds narrative context about redox modulation. BioReason is effectively restating the interpro2go signal with additional mechanistic inference, rather than providing fundamentally new insight.

Notes on thinking trace

The thinking trace demonstrates competent domain-by-domain reasoning, proceeding from N-terminal to C-terminal. The causal logic linking heparin binding and Kunitz domains to regulated proteolysis is sound. The trace correctly avoids naming APP or Alzheimer disease despite the amyloid-beta domain being diagnostic, staying grounded in the sequence-to-function inference framework.

📄 View Raw YAML

id: P05067
gene_symbol: APP
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'Amyloid-beta precursor protein (APP) is a type I transmembrane protein
  that undergoes complex proteolytic processing to generate multiple bioactive fragments
  with distinct biological functions. APP is a paradigm for regulated intramembrane
  proteolysis (RIP). The protein has both alternative splice isoforms (APP695/751/770
  differing in presence of KPI domain) and undergoes proteolytic cleavage via two
  competing pathways: (1) non-amyloidogenic (alpha-secretase) producing neuroprotective
  sAPPalpha, and (2) amyloidogenic (beta-secretase/BACE1) producing Abeta peptides
  associated with Alzheimer''s disease. Full-length APP functions as a cell adhesion
  molecule, regulates neurite outgrowth, synapse formation, and copper/zinc homeostasis.
  The AICD fragment functions in nuclear signaling. Key biological insight: sAPPalpha
  is NEUROPROTECTIVE while Abeta is NEUROTOXIC - antagonistic functions from the same
  gene product. CRITICAL: Many annotations conflate full-length APP, splice isoforms,
  and cleavage products. Human APP is directly relevant to Alzheimer''s disease pathology
  with familial mutations (Swedish, London, etc.) that increase Abeta42/40 ratio.'
alternative_products:
- name: APP770 (PreA4 770)
  id: P05067-1
- name: APP305
  id: P05067-2
  sequence_note: VSP_000005, VSP_000006
- name: L-APP677
  id: P05067-3
  sequence_note: VSP_000002, VSP_000004, VSP_000009
- name: APP695 (PreA4 695)
  id: P05067-4
  sequence_note: VSP_000002, VSP_000004
- name: L-APP696
  id: P05067-5
  sequence_note: VSP_000002, VSP_000003, VSP_000009
- name: APP714
  id: P05067-6
  sequence_note: VSP_000002, VSP_000003
- name: L-APP733
  id: P05067-7
  sequence_note: VSP_000007, VSP_000008, VSP_000009
- name: APP751 (PreA4 751)
  id: P05067-8
  sequence_note: VSP_000007, VSP_000008
- name: L-APP752
  id: P05067-9
  sequence_note: VSP_000009
- name: APP639
  id: P05067-10
  sequence_note: VSP_009116, VSP_009117, VSP_009118
- name: '11'
  id: P05067-11
  sequence_note: VSP_045446, VSP_045447
functional_isoforms:
- id: APP_695_NEURONAL
  name: APP695 (Neuronal)
  type: SPLICE_CLASS
  maps_to:
  - type: UNIPROT_ISOFORM
    ids:
    - P05067-4
  description: 'Brain-predominant isoform lacking the KPI (Kunitz protease inhibitor)
    domain encoded by exon 7. APP695 is the major isoform in neurons and is the primary
    substrate for amyloidogenic processing in the brain. Does NOT have serine protease
    inhibitor activity. The ratio of APP695 to KPI-containing isoforms decreases with
    aging and in Alzheimer''s disease.

    '
  isoform_specific_terms:
  - id: GO:0031175
    label: neuron projection development
- id: APP_KPI_CONTAINING
  name: APP751/770 (KPI-containing)
  type: SPLICE_CLASS
  maps_to:
  - type: UNIPROT_ISOFORM
    ids:
    - P05067-1
    - P05067-8
  description: 'Peripheral isoforms containing the KPI (Kunitz protease inhibitor)
    domain. APP770 (P05067-1) also has the OX-2 domain. These isoforms have serine
    protease inhibitor activity that APP695 lacks. Predominantly expressed in non-neuronal
    tissues. May regulate coagulation and inflammation.

    '
  isoform_specific_terms:
  - id: GO:0004867
    label: serine-type endopeptidase inhibitor activity
- id: APP_SAPP_ALPHA
  name: sAPPalpha (Soluble APP-alpha)
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids:
    - PRO_0000000088
    residues: 18-687
  description: 'NEUROPROTECTIVE ectodomain released by alpha-secretase (ADAM10/17)
    cleavage. sAPPalpha promotes neurite outgrowth, synaptogenesis, and neuronal survival.
    Has 10-100x higher neurotrophic activity than sAPPbeta. The alpha-secretase pathway
    PRECLUDES Abeta generation - thus sAPPalpha represents the "non-amyloidogenic"
    pathway. Enhancing alpha-secretase is a therapeutic strategy for Alzheimer''s
    disease.

    '
  isoform_specific_terms:
  - id: GO:0043524
    label: negative regulation of neuron apoptotic process
  - id: GO:0031175
    label: neuron projection development
- id: APP_SAPP_BETA
  name: sAPPbeta (Soluble APP-beta)
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids:
    - PRO_0000000089
    residues: 18-671
  description: 'Ectodomain released by beta-secretase (BACE1) cleavage. Unlike sAPPalpha,
    sAPPbeta has REDUCED neurotrophic activity and may promote apoptosis by binding
    to DR6 (death receptor 6). This is the first step of the AMYLOIDOGENIC pathway
    that leads to Abeta generation.

    '
- id: APP_ABETA42
  name: Amyloid-beta 42 (Abeta42)
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids:
    - PRO_0000000092
    residues: 672-713
  description: 'NEUROTOXIC peptide - the pathogenic form in Alzheimer''s disease.
    Abeta42 is more aggregation-prone than Abeta40 due to two additional hydrophobic
    C-terminal residues. Forms oligomers and fibrils that cause synaptic dysfunction,
    oxidative stress, and neuron death. The Abeta42/Abeta40 ratio is critical - increased
    ratio (even with normal total Abeta) causes familial AD. ANTAGONISTIC to sAPPalpha
    function - same gene produces both neuroprotective AND neurotoxic products depending
    on processing pathway.

    '
  isoform_specific_terms:
  - id: GO:0043525
    label: positive regulation of neuron apoptotic process
  - id: GO:1990000
    label: amyloid fibril formation
- id: APP_ABETA40
  name: Amyloid-beta 40 (Abeta40)
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids:
    - PRO_0000000091
    residues: 672-711
  description: 'Major Abeta species (90% of Abeta). Less aggregation-prone than Abeta42.
    May actually be protective by competing with Abeta42 for aggregation sites. The
    Abeta42/Abeta40 ratio is more predictive of AD than total Abeta levels.

    '
  isoform_specific_terms:
  - id: GO:1990000
    label: amyloid fibril formation
- id: APP_AICD
  name: AICD (APP Intracellular Domain)
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids:
    - PRO_0000000093
    - PRO_0000000094
    - PRO_0000000095
    residues: 712-770 / 714-770 / 721-770
  description: 'Intracellular fragment released by gamma-secretase cleavage. AICD
    translocates to nucleus with Fe65 and Tip60, where it may act as a transcriptional
    regulator. Proposed targets include EGFR, p53, KAI1/CD82, GSK3B, and neprilysin.
    However, the transcription factor function of AICD remains CONTROVERSIAL - some
    studies suggest nuclear AICD is an artifact of overexpression. AICD is rapidly
    degraded by IDE (insulin-degrading enzyme).

    '
- id: APP_N_APP
  name: N-APP (N-terminal fragment)
  type: CLEAVAGE_PRODUCT
  maps_to:
  - type: UNIPROT_CHAIN
    ids:
    - PRO_0000381966
    residues: 18-286
  description: 'N-terminal fragment that binds DR6 (death receptor 6, TNFRSF21) to
    trigger axon degeneration via caspase-6. Important for developmental axon pruning.
    May contribute to neurodegeneration in disease. Contains the growth factor and
    copper-binding domains.

    '
existing_annotations:
- term:
    id: GO:0007409
    label: axonogenesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation. Full-length APP regulates axon development. APP knockout
      mice show defects in axonogenesis. sAPPalpha promotes neurite outgrowth while
      full-length APP with Fe65/Mena inhibits branching to ensure directional growth.
    action: ACCEPT
    reason: Core biological process. Well-supported by knockout studies and mechanistic
      understanding.
- term:
    id: GO:0007417
    label: central nervous system development
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Phylogenetic inference (IBA) from GO_REF:0000033. IBA annotations undergo
      extensive phylogenetic review and are generally reliable.
    action: ACCEPT
    reason: IBA annotation supported by phylogenetic analysis.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Cellular component annotation supported by APP trafficking and localization
      studies. APP is found in multiple cellular compartments consistent with its
      complex processing pathway (UniProt P05067).
    action: ACCEPT
    reason: Well-documented localization consistent with APP biology.
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Phylogenetic inference (IBA) from GO_REF:0000033. IBA annotations undergo
      extensive phylogenetic review and are generally reliable.
    action: ACCEPT
    reason: IBA annotation supported by phylogenetic analysis.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Cellular component annotation supported by APP trafficking and localization
      studies. APP is found in multiple cellular compartments consistent with its
      complex processing pathway (UniProt P05067).
    action: ACCEPT
    reason: Well-documented localization consistent with APP biology.
- term:
    id: GO:0030546
    label: signaling receptor activator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'Abeta42 activates FPR2 (formyl peptide receptor 2), inducing chemotaxis
      and oxidant stress in phagocytes (PMID:11316806). Note: this is primarily an
      Abeta cleavage product function.'
    action: ACCEPT
    reason: Supported by literature, though applies to Abeta rather than full-length
      APP.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Cellular component annotation supported by APP trafficking and localization
      studies. APP is found in multiple cellular compartments consistent with its
      complex processing pathway (UniProt P05067).
    action: ACCEPT
    reason: Well-documented localization consistent with APP biology.
- term:
    id: GO:0045121
    label: membrane raft
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Cellular component annotation supported by APP trafficking and localization
      studies. APP is found in multiple cellular compartments consistent with its
      complex processing pathway (UniProt P05067).
    action: ACCEPT
    reason: Well-documented localization consistent with APP biology.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Cellular component annotation supported by APP trafficking and localization
      studies. APP is found in multiple cellular compartments consistent with its
      complex processing pathway (UniProt P05067).
    action: ACCEPT
    reason: Well-documented localization consistent with APP biology.
- term:
    id: GO:0004867
    label: serine-type endopeptidase inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'ISOFORM-SPECIFIC: KPI-containing isoforms (APP751/770) only. The Kunitz
      protease inhibitor domain is absent from the neuronal APP695 isoform.'
    action: ACCEPT
    reason: IEA annotation consistent with known APP biology. Note isoform specificity.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: IEA annotation. Secreted sAPPalpha/beta and Abeta are found in extracellular
      region.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: AICD translocates to nucleus with Fe65 and Tip60 for transcriptional
      regulation. However, this remains controversial.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation. APP cytoplasmic domain interacts with multiple adaptor
      proteins.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: IEA annotation. APP is processed in endosomes where BACE1 cleavage occurs.
    action: ACCEPT
    reason: IEA annotation consistent with known APP trafficking.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: IEA annotation. APP is synthesized and processed through ER.
    action: ACCEPT
    reason: IEA annotation consistent with known APP trafficking.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: IEA annotation. APP transits through Golgi during maturation.
    action: ACCEPT
    reason: IEA annotation consistent with known APP trafficking.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: IEA annotation. Full-length APP is a type I transmembrane protein at
      plasma membrane.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0005905
    label: clathrin-coated pit
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation. APP is internalized via clathrin-mediated endocytosis.
    action: ACCEPT
    reason: IEA annotation consistent with known APP trafficking.
- term:
    id: GO:0006897
    label: endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: IEA annotation. APP undergoes internalization via endocytosis.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: 'CLEAVAGE PRODUCT DEPENDENT: Abeta induces apoptosis (neurotoxic), while
      sAPPalpha is neuroprotective. Full-length APP itself has dual roles depending
      on processing pathway.'
    action: ACCEPT
    reason: IEA annotation consistent with APP biology but note cleavage product specificity.
- term:
    id: GO:0007155
    label: cell adhesion
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: IEA annotation. Full-length APP functions as a cell adhesion molecule
      via trans-dimerization.
    action: ACCEPT
    reason: Core function of full-length APP.
- term:
    id: GO:0007219
    label: Notch signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: APP is not a component of the Notch signaling pathway. This IEA annotation
      likely arises because APP and Notch are both substrates of gamma-secretase (presenilin),
      but sharing an enzyme does not make APP part of the Notch pathway. APP has its
      own distinct signaling pathway via AICD.
    action: REMOVE
    reason: APP is a substrate of gamma-secretase but is NOT a participant in Notch
      signaling. The connection is only that they share the same protease. This is
      an incorrect annotation that should be removed.
- term:
    id: GO:0008201
    label: heparin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation. APP ectodomain binds heparin and heparan sulfate proteoglycans.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation. Full-length APP is a type I transmembrane protein at
      cell surface.
    action: ACCEPT
    reason: IEA annotation consistent with known APP localization.
- term:
    id: GO:0010604
    label: positive regulation of macromolecule metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: IEA annotation for positive regulation of macromolecule metabolic process.
      This is extremely broad and does not provide useful functional information about
      APP.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too broad to be informative. Over-annotation.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation. Full-length APP is a type I transmembrane protein.
    action: ACCEPT
    reason: IEA annotation consistent with known APP localization.
- term:
    id: GO:0030414
    label: peptidase inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: 'ISOFORM-SPECIFIC: KPI-containing isoforms (APP751/770) only. The Kunitz
      protease inhibitor domain is absent from neuronal APP695.'
    action: ACCEPT
    reason: IEA annotation consistent with known APP biology. Note isoform specificity.
- term:
    id: GO:0030426
    label: growth cone
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation. APP is localized to growth cones and regulates axon guidance.
    action: ACCEPT
    reason: IEA annotation consistent with known APP localization and function.
- term:
    id: GO:0031091
    label: platelet alpha granule
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: IEA annotation. APP is expressed in platelets and stored in alpha granules.
    action: ACCEPT
    reason: IEA annotation consistent with known APP expression.
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation. APP is transported in vesicles along axons.
    action: ACCEPT
    reason: IEA annotation consistent with known APP trafficking.
- term:
    id: GO:0043005
    label: neuron projection
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: IEA annotation. APP is transported to and localized in neuron projections.
    action: ACCEPT
    reason: IEA annotation consistent with known APP localization.
- term:
    id: GO:0043204
    label: perikaryon
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: IEA annotation. APP is found in neuronal cell bodies.
    action: ACCEPT
    reason: IEA annotation consistent with known APP localization.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: IEA annotation. APP binds copper and zinc via its ectodomain and regulates
      metal homeostasis.
    action: ACCEPT
    reason: Core function of APP. Well documented.
- term:
    id: GO:0046914
    label: transition metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation. APP binds copper and zinc (transition metals) via its
      ectodomain.
    action: ACCEPT
    reason: Core function of APP. Well documented.
- term:
    id: GO:0051246
    label: regulation of protein metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: IEA annotation for regulation of protein metabolic process. This is very
      broad and does not provide useful functional information about APP.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too broad to be informative. Over-annotation.
- term:
    id: GO:0140677
    label: molecular function activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: IEA annotation for molecular function activator activity. This is extremely
      broad and does not specify what molecular function APP activates. Not informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too broad to be informative. Over-annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10677483
  review:
    summary: IPI protein binding annotation. BACE1 (memapsin 2) cleaves APP at the
      beta-secretase site. Functional interaction for APP processing.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - the specific interaction is with
      BACE1.
    supported_by:
    - reference_id: PMID:10677483
      supporting_text: Human aspartic protease memapsin 2 cleaves the beta-secretase
        site of beta-amyloid precursor protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10681545
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:10681545
      supporting_text: beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine
        receptor with high affinity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11278849
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:11278849
      supporting_text: 2001 Feb 20. beta -Amyloid peptide-induced apoptosis regulated
        by a novel protein containing a g protein activation module.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11297421
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:11297421
      supporting_text: Apolipoprotein A-I directly interacts with amyloid precursor
        protein and inhibits A beta aggregation and toxicity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11724784
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:11724784
      supporting_text: Nov 27. Jun NH2-terminal kinase (JNK) interacting protein 1
        (JIP1) binds the cytoplasmic domain of the Alzheimer's beta-amyloid precursor
        protein (APP).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11877420
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:11877420
      supporting_text: 2002 Mar 4. Tyrosine phosphorylation of the beta-amyloid precursor
        protein cytoplasmic tail promotes interaction with Shc.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12485888
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:12485888
      supporting_text: Signal transduction through tyrosine-phosphorylated carboxy-terminal
        fragments of APP via an enhanced interaction with Shc/Grb2 adaptor proteins
        in reactive astrocytes of Alzheimer's disease brain.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12901838
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:12901838
      supporting_text: Presenilin-1 interacts directly with the beta-site amyloid
        protein precursor cleaving enzyme (BACE1).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15896298
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:15896298
      supporting_text: In cerebrospinal fluid ER chaperones ERp57 and calreticulin
        bind beta-amyloid.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16027166
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:16027166
      supporting_text: 2005 Jul 18. BRI2 interacts with amyloid precursor protein
        (APP) and regulates amyloid beta (Abeta) production.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16049941
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:16049941
      supporting_text: A pilot proteomic study of amyloid precursor interactors in
        Alzheimer's disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16174740
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:16174740
      supporting_text: Neuronal sorting protein-related receptor sorLA/LR11 regulates
        processing of the amyloid precursor protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16286452
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:16286452
      supporting_text: Nov 10. Gerstmann-Sträussler-Scheinker disease amyloid protein
        polymerizes according to the "dock-and-lock" model.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16374483
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:16374483
      supporting_text: Neurofibromatosis type 1 protein and amyloid precursor protein
        interact in normal human melanocytes and colocalize with melanosomes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16446437
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:16446437
      supporting_text: Abeta and tau form soluble complexes that may promote self
        aggregation of both into the insoluble forms observed in Alzheimer's disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16480949
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:16480949
      supporting_text: The intracellular domain of amyloid precursor protein interacts
        with flotillin-1, a lipid raft protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16554819
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:16554819
      supporting_text: The prolyl isomerase Pin1 regulates amyloid precursor protein
        processing and amyloid-beta production.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17112520
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:17112520
      supporting_text: 'Epub 2006 Nov 9. Aluminum inhibits proteolytic degradation
        of amyloid beta peptide by cathepsin D: a potential link between aluminum
        accumulation and neuritic plaque deposition.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17709753
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:17709753
      supporting_text: Amyolid precursor protein mediates presynaptic localization
        and activity of the high-affinity choline transporter.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20195357
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:20195357
      supporting_text: A comprehensive resource of interacting protein regions for
        refining human transcription factor networks.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20811458
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:20811458
      supporting_text: Gamma-secretase activating protein is a therapeutic target
        for Alzheimer's disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20817278
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:20817278
      supporting_text: Iron-export ferroxidase activity of β-amyloid precursor protein
        is inhibited by zinc in Alzheimer's disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20828565
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:20828565
      supporting_text: Epub 2010 Sep 7. An aminopeptidase from Streptomyces sp.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21163940
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:21163940
      supporting_text: Interactome mapping suggests new mechanistic details underlying
        Alzheimer's disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:2119582
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:2119582
      supporting_text: Transforming growth factor-beta bound to soluble derivatives
        of the beta amyloid precursor protein of Alzheimer's disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21293490
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:21293490
      supporting_text: Mediator is a transducer of amyloid-precursor-protein-dependent
        nuclear signalling.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22730553
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:22730553
      supporting_text: Open-closed motion of Mint2 regulates APP metabolism.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22801501
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:22801501
      supporting_text: A mutation in APP protects against Alzheimer's disease and
        age-related cognitive decline.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23585889
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:23585889
      supporting_text: Generation of amyloid-β is reduced by the interaction of calreticulin
        with amyloid precursor protein, presenilin and nicastrin.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24028865
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:24028865
      supporting_text: Impact of the cellular prion protein on amyloid-β and 3PO-tau
        processing.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24284412
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:24284412
      supporting_text: 2013 Nov 27. Amyloid beta a4 precursor protein-binding family
        B member 1 (FE65) interactomics revealed synaptic vesicle glycoprotein 2A
        (SV2A) and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) as
        new binding proteins in the human brain.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24867889
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:24867889
      supporting_text: sAPP modulates iron efflux from brain microvascular endothelial
        cells by stabilizing the ferrous iron exporter ferroportin.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25241761
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:25241761
      supporting_text: Oct 9. Using an in situ proximity ligation assay to systematically
        profile endogenous protein-protein interactions in a pathway network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25959826
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:25959826
      supporting_text: 2015 May 7. Quantitative interaction proteomics of neurodegenerative
        disease proteins.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:26496610
      supporting_text: Oct 22. A human interactome in three quantitative dimensions
        organized by stoichiometries and abundances.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29423001
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:29423001
      supporting_text: Hypoxia increases amyloid-β level in exosomes by enhancing
        the interaction between CD147 and Hook1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29578633
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:29578633
      supporting_text: Probing the Mint2 Protein-Protein Interaction Network Relevant
        to the Pathophysiology of Alzheimer's Disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30086173
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:30086173
      supporting_text: eCollection 2018. TMEM30A is a candidate interacting partner
        for the β-carboxyl-terminal fragment of amyloid-β precursor protein in endosomes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30538620
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:30538620
      supporting_text: eCollection 2018. Visualization of Alzheimer's Disease Related
        α-/β-/γ-Secretase Ternary Complex by Bimolecular Fluorescence Complementation
        Based Fluorescence Resonance Energy Transfer.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31413325
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:31413325
      supporting_text: HENA, heterogeneous network-based data set for Alzheimer's
        disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome Mapping Provides a Network of Neurodegenerative
        Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: 2021 May 6. Dual proteome-scale networks reveal cell-specific
        remodeling of the human interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34446781
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:34446781
      supporting_text: First identification of ITM2B interactome in the human retina.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35063084
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:35063084
      supporting_text: 2022 Jan 20. Tau interactome maps synaptic and mitochondrial
        processes associated with neurodegeneration.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35914814
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:35914814
      supporting_text: 'Chr21 protein-protein interactions: enrichment in proteins
        involved in intellectual disability, autism, and late-onset Alzheimer''s disease.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35922511
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:35922511
      supporting_text: Aug 3. A physical wiring diagram for the human immune system.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Apr 9. Multimodal cell maps as a foundation for structural
        and functional genomics.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8855266
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:8855266
      supporting_text: Association of a novel human FE65-like protein with the cytoplasmic
        domain of the beta-amyloid precursor protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8887653
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:8887653
      supporting_text: The phosphotyrosine interaction domains of X11 and FE65 bind
        to distinct sites on the YENPTY motif of amyloid precursor protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9223340
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:9223340
      supporting_text: 'Interaction between amyloid precursor protein and presenilins
        in mammalian cells: implications for the pathogenesis of Alzheimer disease.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9338779
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:9338779
      supporting_text: An intracellular protein that binds amyloid-beta peptide and
        mediates neurotoxicity in Alzheimer's disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9461550
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:9461550
      supporting_text: 'Fe65L2: a new member of the Fe65 protein family interacting
        with the intracellular domain of the Alzheimer''s beta-amyloid precursor protein.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10673326
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:10673326
      supporting_text: Agrin binds to beta-amyloid (Abeta), accelerates abeta fibril
        formation, and is localized to Abeta deposits in Alzheimer's disease brain.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11756426
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:11756426
      supporting_text: Dec 27. Amyloid beta binds trimers as well as monomers of the
        75-kDa neurotrophin receptor and activates receptor signaling.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15615705
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:15615705
      supporting_text: 2004 Dec 21. CLAC binds to amyloid beta peptides through the
        positively charged amino acid cluster within the collagenous domain 1 and
        inhibits formation of amyloid fibrils.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17051221
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:17051221
      supporting_text: Structures of human insulin-degrading enzyme reveal a new substrate
        recognition mechanism.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17116874
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:17116874
      supporting_text: Blocking the apolipoprotein E/amyloid-beta interaction as a
        potential therapeutic approach for Alzheimer's disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18806802
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:18806802
      supporting_text: Cyclophilin D deficiency attenuates mitochondrial and neuronal
        perturbation and ameliorates learning and memory in Alzheimer's disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22179788
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:22179788
      supporting_text: The extracellular chaperone clusterin sequesters oligomeric
        forms of the amyloid-β(1-40) peptide.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22528093
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:22528093
      supporting_text: Search for amyloid-binding proteins by affinity chromatography.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24931469
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:24931469
      supporting_text: 2014 Jun 12. Molecular basis of substrate recognition and degradation
        by human presequence protease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25643321
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:25643321
      supporting_text: Feb 2. Structural basis for amyloidogenic peptide recognition
        by sorLA.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25897080
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:25897080
      supporting_text: 2015 Apr 20. Sequential Amyloid-β Degradation by the Matrix
        Metalloproteases MMP-2 and MMP-9.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26618561
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:26618561
      supporting_text: Epub 2015 Dec 15. Direct High Affinity Interaction between
        Aβ42 and GSK3α Stimulates Hyperphosphorylation of Tau.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30158114
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:30158114
      supporting_text: TLR5 decoy receptor as a novel anti-amyloid therapeutic for
        Alzheimer's disease.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16286452
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:16286452
      supporting_text: Nov 10. Gerstmann-Sträussler-Scheinker disease amyloid protein
        polymerizes according to the "dock-and-lock" model.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:18805418
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:18805418
      supporting_text: 'Epub 2008 Sep 19. In vitro perturbation of aggregation processes
        in beta-amyloid peptides: a spectroscopic study.'
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19549187
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:19549187
      supporting_text: 2009 Jun 22. Quenched hydrogen/deuterium exchange NMR characterization
        of amyloid-beta peptide aggregates formed in the presence of Cu2+ or Zn2+.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19754881
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:19754881
      supporting_text: 2009 Sep 15. The thioflavin T fluorescence assay for amyloid
        fibril detection can be biased by the presence of exogenous compounds.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:20573181
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:20573181
      supporting_text: 2010 Jun 22. Progressive accumulation of amyloid-beta oligomers
        in Alzheimer's disease and in amyloid precursor protein transgenic mice is
        accompanied by selective alterations in synaptic scaffold proteins.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:20818335
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:20818335
      supporting_text: Neurotoxicity of Alzheimer's disease Aβ peptides is induced
        by small changes in the Aβ42 to Aβ40 ratio.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:21113149
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:21113149
      supporting_text: Reversing EphB2 depletion rescues cognitive functions in Alzheimer
        model.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:21205198
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:21205198
      supporting_text: 2011 Jan 17. Lysophosphatidylcholine modulates fibril formation
        of amyloid beta peptide.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:21320494
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:21320494
      supporting_text: 2011 Feb 12. Lipid matrix plays a role in Abeta fibril kinetics
        and morphology.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:21527912
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:21527912
      supporting_text: Extracellular phosphorylation of the amyloid β-peptide promotes
        formation of toxic aggregates during the pathogenesis of Alzheimer's disease.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:22200570
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:22200570
      supporting_text: 2011 Dec 23. Effect of N-homocysteinylation on physicochemical
        and cytotoxic properties of amyloid β-peptide.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:22584060
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:22584060
      supporting_text: Epub 2012 May 11. Dimeric structure of transmembrane domain
        of amyloid precursor protein in micellar environment.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:23103738
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:23103738
      supporting_text: Epub 2012 Oct 24. A comparative analysis of the aggregation
        behavior of amyloid-β peptide variants.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:23353684
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:23353684
      supporting_text: 2013 Jan 23. Protease-activated alpha-2-macroglobulin can inhibit
        amyloid formation via two distinct mechanisms.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:23416305
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:23416305
      supporting_text: 2013 Feb 15. Interaction between soluble Aβ-(1-40) monomer
        and Aβ-(1-42) fibrils probed by paramagnetic relaxation enhancement.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:23551356
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:23551356
      supporting_text: N-terminal domain of Pyrococcus furiosus l-asparaginase functions
        as a non-specific, stable, molecular chaperone.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:23603391
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:23603391
      supporting_text: 2013 Apr 18. NMR characterization of the interaction of GroEL
        with amyloid β as a model ligand.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:23907009
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:23907009
      supporting_text: Epub 2013 Jul 29. Isobavachalcone and bavachinin from Psoraleae
        Fructus modulate Aβ42 aggregation process through different mechanisms in
        vitro.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:24065130
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:24065130
      supporting_text: Amyloid-β oligomers induce synaptic damage via Tau-dependent
        microtubule severing by TTLL6 and spastin.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:24720730
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:24720730
      supporting_text: The coexistence of an equal amount of Alzheimer's amyloid-β
        40 and 42 forms structurally stable and toxic oligomers through a distinct
        pathway.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:28882996
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:28882996
      supporting_text: Sep 7. Fibril structure of amyloid-β(1-42) by cryo-electron
        microscopy.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:17116874
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:17116874
      supporting_text: Blocking the apolipoprotein E/amyloid-beta interaction as a
        potential therapeutic approach for Alzheimer's disease.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:18059284
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:18059284
      supporting_text: Evidence of fibril-like β-sheet structures in a neurotoxic
        amyloid intermediate of Alzheimer's β-amyloid.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:18483195
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:18483195
      supporting_text: Paired beta-sheet structure of an Abeta(1-40) amyloid fibril
        revealed by electron microscopy.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:18499799
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:18499799
      supporting_text: Two-dimensional infrared spectra of isotopically diluted amyloid
        fibrils from Abeta40.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19304802
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:19304802
      supporting_text: Synaptic transmission block by presynaptic injection of oligomeric
        amyloid beta.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19458258
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:19458258
      supporting_text: Alpha-helix targeting reduces amyloid-beta peptide toxicity.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19706468
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:19706468
      supporting_text: Structure-neurotoxicity relationships of amyloid beta-protein
        oligomers.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19706519
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:19706519
      supporting_text: Measurement of amyloid fibril mass-per-length by tilted-beam
        transmission electron microscopy.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19841277
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:19841277
      supporting_text: Site-specific modification of Alzheimer's peptides by cholesterol
        oxidation products enhances aggregation energetics and neurotoxicity.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:20133839
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:20133839
      supporting_text: Mechanism of amyloid plaque formation suggests an intracellular
        basis of Abeta pathogenicity.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:22036569
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:22036569
      supporting_text: Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent
        β-amyloid generation.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:22179788
  review:
    summary: Abeta self-associates forming dimers and higher oligomers.
    action: ACCEPT
    reason: Direct single-molecule fluorescence demonstration of Abeta oligomerization.
    supported_by:
    - reference_id: PMID:22179788
      supporting_text: Aβ(1-40) forms a heterogeneous distribution of small oligomers
        (from dimers to 50-mers)
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25543257
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:25543257
      supporting_text: Dec 24. Modeling an in-register, parallel "iowa" aβ fibril
        structure using solid-state NMR data from labeled samples with rosetta.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:30158114
  review:
    summary: IPI annotation. APP dimerization (homodimerization) is well-established
      and functionally relevant for cell adhesion and processing.
    action: ACCEPT
    reason: APP homodimerization is a core function. More informative than generic
      protein binding.
    supported_by:
    - reference_id: PMID:30158114
      supporting_text: TLR5 decoy receptor as a novel anti-amyloid therapeutic for
        Alzheimer's disease.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0006816
    label: calcium ion transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for calcium ion transport. APP is not a calcium transporter.
      Abeta peptides can form calcium-permeable pores in membranes and Abeta oligomers
      disrupt calcium homeostasis, but APP itself does not transport calcium. This
      is an indirect effect of cleavage products.
    action: MARK_AS_OVER_ANNOTATED
    reason: APP is not a calcium transporter. The calcium effects are indirect, mediated
      by Abeta pore formation and signaling disruption. Over-annotation.
- term:
    id: GO:0007611
    label: learning or memory
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for learning or memory. APP and its cleavage products
      (especially Abeta oligomers) affect learning and memory, but this is a downstream
      phenotypic consequence of APP processing rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: learning or memory is a downstream consequence of APP/Abeta biology. Important
      for disease relevance but not a core function. Keep as non-core.
- term:
    id: GO:0010288
    label: response to lead ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for response to lead ion. Lead exposure has been shown
      to increase APP expression and Abeta production, but this is a response to an
      environmental toxin rather than a core function.
    action: KEEP_AS_NON_CORE
    reason: Response to lead ion is an environmental response, not a core function
      of APP. Keep as non-core.
- term:
    id: GO:0016504
    label: peptidase activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for peptidase activator activity. It is unclear what specific
      peptidase APP activates. APP is itself a substrate of multiple peptidases (alpha-,
      beta-, gamma-secretases) but the mechanism of direct peptidase activation is
      not well characterized.
    action: UNDECIDED
    reason: Unclear molecular basis for peptidase activator activity. APP is a protease
      substrate, not clearly a protease activator. Needs further evidence.
- term:
    id: GO:0030424
    label: axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0036269
    label: swimming behavior
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: ISS annotation for swimming behavior based on mouse APP knockout/transgenic
      studies. These behavioral phenotypes reflect pleiotropic downstream effects
      of APP loss or Abeta overexpression in mice rather than a core molecular function
      of APP.
    action: KEEP_AS_NON_CORE
    reason: Behavioral phenotype (swimming behavior) observed in mouse models. Not
      a core function of APP but a downstream consequence. Keep as non-core.
- term:
    id: GO:0043523
    label: regulation of neuron apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0044304
    label: main axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0045471
    label: response to ethanol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0051247
    label: positive regulation of protein metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for positive regulation of protein metabolic process.
      Very broad term that does not provide useful information about APP function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Too broad to be informative. Over-annotation.
- term:
    id: GO:0070555
    label: response to interleukin-1
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0070851
    label: growth factor receptor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for growth factor receptor binding. The specific growth
      factor receptor that APP binds is unclear. sAPPalpha has growth factor-like
      properties but the receptor is not well defined.
    action: UNDECIDED
    reason: Unclear which growth factor receptor APP binds. Needs further evidence.
- term:
    id: GO:0071280
    label: cellular response to copper ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0071287
    label: cellular response to manganese ion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0071320
    label: cellular response to cAMP
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0071874
    label: cellular response to norepinephrine stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0097449
    label: astrocyte projection
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0098992
    label: neuronal dense core vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0110088
    label: hippocampal neuron apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation for hippocampal neuron apoptotic process. This is an overly
      specific term for Abeta-mediated neurotoxicity. The neurotoxic effect of Abeta
      is well established but this is a pathological consequence, not a core function
      of APP.
    action: KEEP_AS_NON_CORE
    reason: Pathological consequence of Abeta accumulation, not a core function. Overly
      specific cell-type qualification. Keep as non-core.
- term:
    id: GO:1990090
    label: cellular response to nerve growth factor stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:1990418
    label: response to insulin-like growth factor stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:1990761
    label: growth cone lamellipodium
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:1990812
    label: growth cone filopodium
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA annotation based on electronic inference. Consistent with APP biology.
    action: ACCEPT
    reason: IEA annotation consistent with known APP functions.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: NAS
  original_reference_id: PMID:18568035
  isoform: P05067-PRO_0000000093
  review:
    summary: NAS annotation for Abeta localization in extracellular space. Shankar
      et al. (2008) extracted soluble Abeta oligomers from AD brain cortex, demonstrating
      extracellular presence.
    action: ACCEPT
    reason: Annotation correctly targets Abeta cleavage product (PRO_0000000093) and
      extracellular localization is supported by extraction from brain tissue.
    supported_by:
    - reference_id: PMID:18568035
      supporting_text: We extracted soluble amyloid-beta protein (Abeta) oligomers
        directly from the cerebral cortex of subjects with Alzheimer's disease.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: NAS
  original_reference_id: PMID:18568035
  isoform: P05067-PRO_0000000093
  review:
    summary: NAS annotation for Abeta at plasma membrane. Abeta oligomers act at synaptic
      sites, consistent with membrane association.
    action: ACCEPT
    reason: Annotation correctly targets Abeta cleavage product. Membrane association
      implied by synaptic site of action, consistent with other evidence for plasma
      membrane localization.
    supported_by:
    - reference_id: PMID:18568035
      supporting_text: The oligomers potently inhibited long-term potentiation (LTP),
        enhanced long-term depression (LTD) and reduced dendritic spine density in
        normal rodent hippocampus.
- term:
    id: GO:0043408
    label: regulation of MAPK cascade
  evidence_type: ISS
  original_reference_id: GO_REF:0000114
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0045666
    label: positive regulation of neuron differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000114
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:1900272
    label: negative regulation of long-term synaptic potentiation
  evidence_type: IDA
  original_reference_id: PMID:18568035
  isoform: P05067-PRO_0000000093
  review:
    summary: IDA annotation for Abeta-mediated LTP inhibition. Shankar et al. (2008)
      demonstrated that Abeta oligomers extracted directly from AD brains potently
      inhibited LTP in rodent hippocampus. Crucially, this effect was specifically
      attributable to Abeta DIMERS, not monomers or higher-order aggregates.
    action: ACCEPT
    reason: Well-supported IDA annotation correctly targeting Abeta cleavage product.
      This is a core synaptotoxic function of Abeta dimers.
    supported_by:
    - reference_id: PMID:18568035
      supporting_text: The oligomers potently inhibited long-term potentiation (LTP),
        enhanced long-term depression (LTD) and reduced dendritic spine density in
        normal rodent hippocampus
- term:
    id: GO:1900272
    label: negative regulation of long-term synaptic potentiation
  evidence_type: NAS
  original_reference_id: PMID:19242475
  review:
    summary: NAS annotation based on author statement.
    action: ACCEPT
    reason: NAS annotation supported by literature.
    supported_by:
    - reference_id: PMID:19242475
      supporting_text: Cellular prion protein mediates impairment of synaptic plasticity
        by amyloid-beta oligomers.
- term:
    id: GO:1900454
    label: positive regulation of long-term synaptic depression
  evidence_type: IDA
  original_reference_id: PMID:18568035
  isoform: P05067-PRO_0000000093
  review:
    summary: IDA annotation for Abeta-mediated LTD enhancement. Shankar et al. (2008)
      showed that Abeta dimers from AD brains enhanced LTD in rodent hippocampus.
      The mechanism requires metabotropic glutamate receptors (mGluRs).
    action: ACCEPT
    reason: Well-supported IDA annotation correctly targeting Abeta cleavage product.
      LTD enhancement is a core synaptotoxic function of Abeta dimers.
    supported_by:
    - reference_id: PMID:18568035
      supporting_text: The oligomers potently inhibited long-term potentiation (LTP),
        enhanced long-term depression (LTD) and reduced dendritic spine density in
        normal rodent hippocampus
- term:
    id: GO:1900454
    label: positive regulation of long-term synaptic depression
  evidence_type: NAS
  original_reference_id: PMID:19242475
  review:
    summary: NAS annotation based on author statement.
    action: ACCEPT
    reason: NAS annotation supported by literature.
    supported_by:
    - reference_id: PMID:19242475
      supporting_text: Cellular prion protein mediates impairment of synaptic plasticity
        by amyloid-beta oligomers.
- term:
    id: GO:1902951
    label: negative regulation of dendritic spine maintenance
  evidence_type: IDA
  original_reference_id: PMID:18568035
  isoform: P05067-PRO_0000000093
  review:
    summary: IDA annotation for Abeta-mediated spine loss. Shankar et al. (2008) showed
      that Abeta oligomers from AD brains reduced dendritic spine density. Effects
      specifically attributable to Abeta dimers and require NMDA receptors.
    action: ACCEPT
    reason: Well-supported IDA annotation correctly targeting Abeta cleavage product.
      Spine loss is a core synaptotoxic function of Abeta dimers.
    supported_by:
    - reference_id: PMID:18568035
      supporting_text: The oligomers potently inhibited long-term potentiation (LTP),
        enhanced long-term depression (LTD) and reduced dendritic spine density in
        normal rodent hippocampus
- term:
    id: GO:1902951
    label: negative regulation of dendritic spine maintenance
  evidence_type: NAS
  original_reference_id: PMID:22820466
  review:
    summary: NAS annotation based on author statement.
    action: ACCEPT
    reason: NAS annotation supported by literature.
    supported_by:
    - reference_id: PMID:22820466
      supporting_text: Alzheimer amyloid-β oligomer bound to postsynaptic prion protein
        activates Fyn to impair neurons.
- term:
    id: GO:0043525
    label: positive regulation of neuron apoptotic process
  evidence_type: IGI
  original_reference_id: PMID:23164821
  review:
    summary: IGI annotation for positive regulation of neuron apoptotic process. Abeta
      and gamma-CTF fragments promote neuronal apoptosis, but this is a pathological
      consequence of aberrant APP processing rather than a core physiological function.
    action: KEEP_AS_NON_CORE
    reason: Neurotoxicity is a pathological consequence of Abeta, not a core APP function.
      Keep as non-core.
    supported_by:
    - reference_id: PMID:23164821
      supporting_text: silencing of DKK1 blocks Aβ neurotoxicity
- term:
    id: GO:0032224
    label: positive regulation of synaptic transmission, cholinergic
  evidence_type: IDA
  original_reference_id: PMID:33239400
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:33239400
      supporting_text: oAβ42 activates both homomeric α7- and heteromeric α7β2-nAChR
        subtypes while preferentially enhancing α7β2-nAChR open-dwell times
- term:
    id: GO:0043083
    label: synaptic cleft
  evidence_type: TAS
  original_reference_id: PMID:33239400
  review:
    summary: TAS annotation based on author statement in referenced publication.
    action: ACCEPT
    reason: TAS annotation supported by literature.
    supported_by:
    - reference_id: PMID:33239400
      supporting_text: the oligomeric form of amyloid-β (oAβ42), interacting with
        α7-containing nicotinic acetylcholine receptor (nAChR) subtypes
- term:
    id: GO:0048018
    label: receptor ligand activity
  evidence_type: IDA
  original_reference_id: PMID:33239400
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:33239400
      supporting_text: these data provide a molecular mechanism supporting a role
        for α7β2-nAChR in mediating the effects of oAβ42
- term:
    id: GO:0106003
    label: amyloid-beta complex
  evidence_type: IDA
  original_reference_id: PMID:33239400
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:33239400
      supporting_text: the oligomeric form of amyloid-β (oAβ42)
- term:
    id: GO:0031901
    label: early endosome membrane
  evidence_type: IDA
  original_reference_id: PMID:16174740
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:16174740
      supporting_text: Neuronal sorting protein-related receptor sorLA/LR11 regulates
        processing of the amyloid precursor protein.
- term:
    id: GO:0048018
    label: receptor ligand activity
  evidence_type: IDA
  original_reference_id: PMID:16174740
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:16174740
      supporting_text: Neuronal sorting protein-related receptor sorLA/LR11 regulates
        processing of the amyloid precursor protein.
- term:
    id: GO:1904646
    label: cellular response to amyloid-beta
  evidence_type: IDA
  original_reference_id: PMID:29518356
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:29518356
      supporting_text: TREM2 Is a Receptor for β-Amyloid that Mediates Microglial
        Function.
- term:
    id: GO:1905606
    label: regulation of presynapse assembly
  evidence_type: IMP
  original_reference_id: PMID:19726636
  review:
    summary: IMP annotation based on mutant phenotype analysis.
    action: ACCEPT
    reason: IMP annotation supported by mutant phenotype data.
    supported_by:
    - reference_id: PMID:19726636
      supporting_text: Presynaptic and postsynaptic interaction of the amyloid precursor
        protein promotes peripheral and central synaptogenesis.
- term:
    id: GO:1905606
    label: regulation of presynapse assembly
  evidence_type: IDA
  original_reference_id: PMID:19726636
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:19726636
      supporting_text: Presynaptic and postsynaptic interaction of the amyloid precursor
        protein promotes peripheral and central synaptogenesis.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: IDA
  original_reference_id: PMID:24012003
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:24012003
      supporting_text: Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer
        aβ oligomer bound to cellular prion protein.
- term:
    id: GO:0120283
    label: protein serine/threonine kinase binding
  evidence_type: IPI
  original_reference_id: PMID:24305806
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:24305806
      supporting_text: Pharmacologic inhibition of ROCK2 suppresses amyloid-β production
        in an Alzheimer's disease mouse model.
- term:
    id: GO:0055096
    label: low-density lipoprotein particle mediated signaling
  evidence_type: IDA
  original_reference_id: PMID:26005850
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:26005850
      supporting_text: PICALM regulated PICALM/clathrin-dependent internalization
        of Aβ bound to the low density lipoprotein receptor related protein-1
- term:
    id: GO:0098989
    label: NMDA selective glutamate receptor signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:17360908
  review:
    summary: TAS annotation based on author statement in referenced publication.
    action: ACCEPT
    reason: TAS annotation supported by literature.
    supported_by:
    - reference_id: PMID:17360908
      supporting_text: Natural oligomers of the Alzheimer amyloid-beta protein induce
        reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent
        signaling pathway.
- term:
    id: GO:1902993
    label: positive regulation of amyloid precursor protein catabolic process
  evidence_type: IGI
  original_reference_id: PMID:22406537
  review:
    summary: RAGE-mediated Abeta signaling affects APP processing through beta-secretase
      activity.
    action: ACCEPT
    reason: Study shows RAGE inhibitor reduced beta-secretase activity and Abeta production.
    supported_by:
    - reference_id: PMID:22406537
      supporting_text: In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited
        β-secretase activity and Aβ production and suppressed microglia activation
        and the neuroinflammatory response
- term:
    id: GO:0050850
    label: positive regulation of calcium-mediated signaling
  evidence_type: IGI
  original_reference_id: PMID:22500019
  review:
    summary: IGI annotation for positive regulation of calcium-mediated signaling.
      Abeta disrupts calcium homeostasis. Downstream pathological effect.
    action: KEEP_AS_NON_CORE
    reason: Calcium signaling disruption is a downstream effect of Abeta. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:22500019
      supporting_text: 2012 Apr 12. Amyloid β (Aβ) peptide directly activates amylin-3
        receptor subtype by triggering multiple intracellular signaling pathways.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9839072
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9839072
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:15457210
  review:
    summary: IMP annotation for positive regulation of gene expression. Gene expression
      changes are downstream effects of APP processing and Abeta signaling. Some may
      be mediated by AICD transcriptional regulation (controversial). Not core APP
      function.
    action: KEEP_AS_NON_CORE
    reason: positive regulation of gene expression is a downstream effect. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:15457210
      supporting_text: Double Tgs (mutant APP (mAPP)/RAGE) displayed early abnormalities
        in spatial learning/memory, accompanied by altered activation of markers of
        synaptic plasticity and exaggerated neuropathologic findings, before such
        changes were found in mAPP mice
- term:
    id: GO:1900272
    label: negative regulation of long-term synaptic potentiation
  evidence_type: IGI
  original_reference_id: PMID:15457210
  review:
    summary: IGI annotation from RAGE interaction study. Arancio et al. (2004) showed
      mAPP/RAGE double transgenics have early LTP deficits, but RAGE is the receptor
      mediating Abeta effects. The annotation is technically valid but the mechanism
      is RAGE-dependent.
    action: MARK_AS_OVER_ANNOTATED
    reason: While LTP inhibition occurs in mAPP transgenics, this paper demonstrates
      it is RAGE-mediated. The annotation should ideally be on Abeta (PRO_0000000093)
      not full APP, and notes RAGE dependency.
    supported_by:
    - reference_id: PMID:15457210
      supporting_text: RAGE is a cofactor for Abeta-induced neuronal perturbation
        in a model of Alzheimer's-type pathology
- term:
    id: GO:1901224
    label: positive regulation of non-canonical NF-kappaB signal transduction
  evidence_type: IGI
  original_reference_id: PMID:15457210
  review:
    summary: IGI annotation for positive regulation of non-canonical NF-kappaB signal
      transduction. Abeta-mediated inflammatory signaling. Downstream effect.
    action: KEEP_AS_NON_CORE
    reason: NF-kappaB activation is a downstream inflammatory effect of Abeta. Keep
      as non-core.
    supported_by:
    - reference_id: PMID:15457210
      supporting_text: Receptor for Advanced Glycation Endproducts (RAGE), a multiligand
        receptor in the immunoglobulin superfamily, functions as a signal-transducing
        cell surface acceptor for amyloid-beta peptide (Abeta)
- term:
    id: GO:2000406
    label: positive regulation of T cell migration
  evidence_type: IMP
  original_reference_id: PMID:19660551
  review:
    summary: IMP annotation for positive regulation of T cell migration. These immune/inflammatory
      effects are primarily mediated by Abeta cleavage products activating innate
      immune cells (microglia, astrocytes) rather than representing core functions
      of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (positive regulation of T cell migration)
      reflects downstream Abeta-mediated effects. Not a core function of APP itself.
      Keep as non-core.
    supported_by:
    - reference_id: PMID:19660551
      supporting_text: 2009 Aug 4. Biochemical and immunohistochemical analysis of
        an Alzheimer's disease mouse model reveals the presence of multiple cerebral
        Abeta assembly forms throughout life.
- term:
    id: GO:0007611
    label: learning or memory
  evidence_type: IGI
  original_reference_id: PMID:20164328
  review:
    summary: IGI annotation for learning or memory. APP and its cleavage products
      (especially Abeta oligomers) affect learning and memory, but this is a downstream
      phenotypic consequence of APP processing rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: learning or memory is a downstream consequence of APP/Abeta biology. Important
      for disease relevance but not a core function. Keep as non-core.
    supported_by:
    - reference_id: PMID:20164328
      supporting_text: Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer
        accumulation, exacerbating early-stage cognitive decline and septohippocampal
        pathology in a mouse model of Alzheimer's disease.
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:21857966
  review:
    summary: IGI annotation for regulation of gene expression. Gene expression changes
      are downstream effects of APP processing and Abeta signaling. Some may be mediated
      by AICD transcriptional regulation (controversial). Not core APP function.
    action: KEEP_AS_NON_CORE
    reason: regulation of gene expression is a downstream effect. Keep as non-core.
    supported_by:
    - reference_id: PMID:21857966
      supporting_text: WNT5A signaling contributes to Aβ-induced neuroinflammation
        and neurotoxicity.
- term:
    id: GO:0030111
    label: regulation of Wnt signaling pathway
  evidence_type: IC
  original_reference_id: PMID:21857966
  review:
    summary: IC annotation for regulation of Wnt signaling pathway. APP has been reported
      to interact with Wnt pathway components. Not a core function.
    action: KEEP_AS_NON_CORE
    reason: Wnt signaling regulation is not a core function of APP. Keep as non-core.
    supported_by:
    - reference_id: PMID:21857966
      supporting_text: WNT5A signaling contributes to Aβ-induced neuroinflammation
        and neurotoxicity.
- term:
    id: GO:0046330
    label: positive regulation of JNK cascade
  evidence_type: IGI
  original_reference_id: PMID:23921129
  review:
    summary: IGI annotation for positive regulation of JNK cascade. APP cytoplasmic
      domain interacts with JIP1 and can activate JNK signaling. Downstream signaling
      effect.
    action: KEEP_AS_NON_CORE
    reason: JNK cascade activation is a downstream signaling effect. Keep as non-core.
    supported_by:
    - reference_id: PMID:23921129
      supporting_text: Neuronal FcγRIIb activated ER stress and caspase-12
- term:
    id: GO:0048169
    label: regulation of long-term neuronal synaptic plasticity
  evidence_type: IGI
  original_reference_id: PMID:23921129
  review:
    summary: 'IGI annotation based on genetic interaction evidence. NOTE: Many IGI
      annotations for APP involve Abeta-specific effects from transgenic mouse studies
      and may not represent full-length APP function.'
    action: ACCEPT
    reason: IGI annotation supported by genetic interaction data. Note potential cleavage
      product specificity.
    supported_by:
    - reference_id: PMID:23921129
      supporting_text: Fcgr2b deficiency ameliorated Aβ-induced inhibition of long-term
        potentiation
- term:
    id: GO:0007611
    label: learning or memory
  evidence_type: IGI
  original_reference_id: PMID:20445063
  review:
    summary: IGI annotation for learning or memory. APP and its cleavage products
      (especially Abeta oligomers) affect learning and memory, but this is a downstream
      phenotypic consequence of APP processing rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: learning or memory is a downstream consequence of APP/Abeta biology. Important
      for disease relevance but not a core function. Keep as non-core.
    supported_by:
    - reference_id: PMID:20445063
      supporting_text: Memory impairment in transgenic Alzheimer mice requires cellular
        prion protein.
- term:
    id: GO:0007611
    label: learning or memory
  evidence_type: IGI
  original_reference_id: PMID:24012003
  review:
    summary: IGI annotation for learning or memory. APP and its cleavage products
      (especially Abeta oligomers) affect learning and memory, but this is a downstream
      phenotypic consequence of APP processing rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: learning or memory is a downstream consequence of APP/Abeta biology. Important
      for disease relevance but not a core function. Keep as non-core.
    supported_by:
    - reference_id: PMID:24012003
      supporting_text: Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer
        aβ oligomer bound to cellular prion protein.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:28008308
  review:
    summary: IGI annotation for positive regulation of gene expression. Gene expression
      changes are downstream effects of APP processing and Abeta signaling. Some may
      be mediated by AICD transcriptional regulation (controversial). Not core APP
      function.
    action: KEEP_AS_NON_CORE
    reason: positive regulation of gene expression is a downstream effect. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:28008308
      supporting_text: eCollection 2016. The Protective Role of microRNA-200c in Alzheimer's
        Disease Pathologies Is Induced by Beta Amyloid-Triggered Endoplasmic Reticulum
        Stress.
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:28008308
  review:
    summary: IGI annotation for negative regulation of gene expression. Gene expression
      changes are downstream effects of APP processing and Abeta signaling. Some may
      be mediated by AICD transcriptional regulation (controversial). Not core APP
      function.
    action: KEEP_AS_NON_CORE
    reason: negative regulation of gene expression is a downstream effect. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:28008308
      supporting_text: eCollection 2016. The Protective Role of microRNA-200c in Alzheimer's
        Disease Pathologies Is Induced by Beta Amyloid-Triggered Endoplasmic Reticulum
        Stress.
- term:
    id: GO:0046982
    label: protein heterodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:19660551
  review:
    summary: Abeta forms SDS-stable dimers in J20 transgenic mouse brain.
    action: ACCEPT
    reason: Direct biochemical demonstration of Abeta dimerization.
    supported_by:
    - reference_id: PMID:19660551
      supporting_text: Using an immunoprecipitation/Western blotting technique we
        find an age-dependent increase in Abeta monomer and SDS-stable dimer
- term:
    id: GO:0050808
    label: synapse organization
  evidence_type: IGI
  original_reference_id: PMID:24012003
  review:
    summary: 'IGI annotation based on genetic interaction evidence. NOTE: Many IGI
      annotations for APP involve Abeta-specific effects from transgenic mouse studies
      and may not represent full-length APP function.'
    action: ACCEPT
    reason: IGI annotation supported by genetic interaction data. Note potential cleavage
      product specificity.
    supported_by:
    - reference_id: PMID:24012003
      supporting_text: Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer
        aβ oligomer bound to cellular prion protein.
- term:
    id: GO:0051247
    label: positive regulation of protein metabolic process
  evidence_type: IMP
  original_reference_id: PMID:11404397
  review:
    summary: IMP annotation based on mutant phenotype analysis.
    action: ACCEPT
    reason: IMP annotation supported by mutant phenotype data.
    supported_by:
    - reference_id: PMID:11404397
      supporting_text: 'Beta-amyloid activates the mitogen-activated protein kinase
        cascade via hippocampal alpha7 nicotinic acetylcholine receptors: In vitro
        and in vivo mechanisms related to Alzheimer''s disease.'
- term:
    id: GO:0051262
    label: protein tetramerization
  evidence_type: IPI
  original_reference_id: PMID:19660551
  review:
    summary: Abeta forms multiple assembly forms including oligomers in J20 mouse
      brain.
    action: ACCEPT
    reason: Study shows multiple Abeta assembly forms detected biochemically.
    supported_by:
    - reference_id: PMID:19660551
      supporting_text: These data demonstrate the presence of multiple assembly forms
        of Abeta throughout the life of J20 mice
- term:
    id: GO:0070206
    label: protein trimerization
  evidence_type: IPI
  original_reference_id: PMID:19660551
  review:
    summary: Abeta forms multiple oligomeric assembly forms in J20 mouse brain.
    action: ACCEPT
    reason: Study demonstrates multiple Abeta assembly forms including oligomers.
    supported_by:
    - reference_id: PMID:19660551
      supporting_text: These data demonstrate the presence of multiple assembly forms
        of Abeta throughout the life of J20 mice
- term:
    id: GO:0150003
    label: regulation of spontaneous synaptic transmission
  evidence_type: IGI
  original_reference_id: PMID:15457210
  review:
    summary: Abeta-RAGE interaction affects synaptic plasticity markers in transgenic
      mouse models.
    action: ACCEPT
    reason: Study shows RAGE-mediated Abeta effects on synaptic function.
    supported_by:
    - reference_id: PMID:15457210
      supporting_text: Double Tgs (mutant APP (mAPP)/RAGE) displayed early abnormalities
        in spatial learning/memory, accompanied by altered activation of markers of
        synaptic plasticity and exaggerated neuropathologic findings, before such
        changes were found in mAPP mice
- term:
    id: GO:1905908
    label: positive regulation of amyloid fibril formation
  evidence_type: IMP
  original_reference_id: PMID:19660551
  review:
    summary: IMP annotation for positive regulation of amyloid fibril formation. While
      amyloid fibril formation is central to AD pathology, it is a pathological process
      rather than a core physiological function.
    action: KEEP_AS_NON_CORE
    reason: Amyloid fibril formation is pathological rather than a core physiological
      function. Keep as non-core.
    supported_by:
    - reference_id: PMID:19660551
      supporting_text: biochemical fractionation and ELISA analysis revealed evidence
        of TBS and triton-insoluble sedimentable Abeta aggregates at the earliest
        ages studied
- term:
    id: GO:0034361
    label: very-low-density lipoprotein particle
  evidence_type: IPI
  original_reference_id: PMID:9211985
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:9211985
      supporting_text: when equivalent amounts of apoE3 or E4 were incubated with
        beta-amyloid (A beta), apoE3 formed 20 times as much SDS-stable complex with
        the peptide as apoE4
- term:
    id: GO:0034362
    label: low-density lipoprotein particle
  evidence_type: IPI
  original_reference_id: PMID:9211985
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:9211985
      supporting_text: Lipoproteins isolated from the plasma of individuals homozygous
        for either epsilon2 or epsilon3 were incubated with A beta(1-40)
- term:
    id: GO:0034363
    label: intermediate-density lipoprotein particle
  evidence_type: IPI
  original_reference_id: PMID:9211985
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:9211985
      supporting_text: lipoprotein-associated rabbit apoE (Cys112, Arg158) did bind
        the peptide
- term:
    id: GO:0034364
    label: high-density lipoprotein particle
  evidence_type: IPI
  original_reference_id: PMID:9211985
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:9211985
      supporting_text: ApoE2:A beta complex formation was comparable to apoE3:A beta
        in both native and purified preparations of apoE
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:15447668
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:15447668
      supporting_text: MAPK recruitment by beta-amyloid in organotypic hippocampal
        slice cultures depends on physical state and exposure time.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:22179788
  review:
    summary: Abeta forms dimers as part of its oligomerization pathway.
    action: ACCEPT
    reason: Single-molecule fluorescence shows Abeta forms dimers to 50-mers.
    supported_by:
    - reference_id: PMID:22179788
      supporting_text: Aβ(1-40) forms a heterogeneous distribution of small oligomers
        (from dimers to 50-mers)
- term:
    id: GO:0051260
    label: protein homooligomerization
  evidence_type: IPI
  original_reference_id: PMID:15447668
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:15447668
      supporting_text: MAPK recruitment by beta-amyloid in organotypic hippocampal
        slice cultures depends on physical state and exposure time.
- term:
    id: GO:0051260
    label: protein homooligomerization
  evidence_type: IPI
  original_reference_id: PMID:18602473
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:18602473
      supporting_text: '2008 Jun 17. Aggregation and catabolism of disease-associated
        intra-Abeta mutations: reduced proteolysis of AbetaA21G by neprilysin.'
- term:
    id: GO:0051260
    label: protein homooligomerization
  evidence_type: IPI
  original_reference_id: PMID:22179788
  review:
    summary: Abeta self-associates forming a range of oligomeric species from dimers
      to 50-mers.
    action: ACCEPT
    reason: Direct single-molecule fluorescence characterization of Abeta oligomerization.
    supported_by:
    - reference_id: PMID:22179788
      supporting_text: Aβ(1-40) forms a heterogeneous distribution of small oligomers
        (from dimers to 50-mers)
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:23164821
  review:
    summary: IGI annotation for positive regulation of gene expression. Gene expression
      changes are downstream effects of APP processing and Abeta signaling. Some may
      be mediated by AICD transcriptional regulation (controversial). Not core APP
      function.
    action: KEEP_AS_NON_CORE
    reason: positive regulation of gene expression is a downstream effect. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:23164821
      supporting_text: Aβ induces the neuronal expression of the canonical wnt antagonist,
        Dickkopf-1 (Dkk1)
- term:
    id: GO:1904591
    label: positive regulation of protein import
  evidence_type: IDA
  original_reference_id: PMID:23164821
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:23164821
      supporting_text: We demonstrate that Aβ rapidly targets the clusterin protein,
        causing its intracellular accumulation possibly by blocking its exit from
        neurons
- term:
    id: GO:1990000
    label: amyloid fibril formation
  evidence_type: EXP
  original_reference_id: PMID:26138908
  review:
    summary: EXP annotation based on experimental evidence.
    action: ACCEPT
    reason: EXP annotation supported by direct experimental data.
    supported_by:
    - reference_id: PMID:26138908
      supporting_text: High-resolution NMR characterization of low abundance oligomers
        of amyloid-β without purification.
- term:
    id: GO:1990000
    label: amyloid fibril formation
  evidence_type: EXP
  original_reference_id: PMID:9737846
  review:
    summary: EXP annotation based on experimental evidence.
    action: ACCEPT
    reason: EXP annotation supported by direct experimental data.
    supported_by:
    - reference_id: PMID:9737846
      supporting_text: Solution structure of methionine-oxidized amyloid beta-peptide
        (1-40).
- term:
    id: GO:0007611
    label: learning or memory
  evidence_type: IMP
  original_reference_id: PMID:11880515
  review:
    summary: IMP annotation for learning or memory. APP and its cleavage products
      (especially Abeta oligomers) affect learning and memory, but this is a downstream
      phenotypic consequence of APP processing rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: learning or memory is a downstream consequence of APP/Abeta biology. Important
      for disease relevance but not a core function. Keep as non-core.
    supported_by:
    - reference_id: PMID:11880515
      supporting_text: The relationship between Abeta and memory in the Tg2576 mouse
        model of Alzheimer's disease.
- term:
    id: GO:0007612
    label: learning
  evidence_type: IMP
  original_reference_id: PMID:11140684
  review:
    summary: IMP annotation for learning. APP and its cleavage products (especially
      Abeta oligomers) affect learning and memory, but this is a downstream phenotypic
      consequence of APP processing rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: learning is a downstream consequence of APP/Abeta biology. Important for
      disease relevance but not a core function. Keep as non-core.
    supported_by:
    - reference_id: PMID:11140684
      supporting_text: A learning deficit related to age and beta-amyloid plaques
        in a mouse model of Alzheimer's disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14527950
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:14527950
      supporting_text: 2003 Oct 3. Generation of the beta-amyloid peptide and the
        amyloid precursor protein C-terminal fragment gamma are potentiated by FE65L1.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IDA
  original_reference_id: PMID:14527950
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:14527950
      supporting_text: 2003 Oct 3. Generation of the beta-amyloid peptide and the
        amyloid precursor protein C-terminal fragment gamma are potentiated by FE65L1.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:14527950
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:14527950
      supporting_text: 2003 Oct 3. Generation of the beta-amyloid peptide and the
        amyloid precursor protein C-terminal fragment gamma are potentiated by FE65L1.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:14527950
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:14527950
      supporting_text: 2003 Oct 3. Generation of the beta-amyloid peptide and the
        amyloid precursor protein C-terminal fragment gamma are potentiated by FE65L1.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:29518356
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:29518356
      supporting_text: TREM2 Is a Receptor for β-Amyloid that Mediates Microglial
        Function.
- term:
    id: GO:0048018
    label: receptor ligand activity
  evidence_type: IDA
  original_reference_id: PMID:29518356
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:29518356
      supporting_text: TREM2 Is a Receptor for β-Amyloid that Mediates Microglial
        Function.
- term:
    id: GO:0014005
    label: microglia development
  evidence_type: IGI
  original_reference_id: PMID:22198949
  review:
    summary: IGI annotation for microglia development. These immune/inflammatory effects
      are primarily mediated by Abeta cleavage products activating innate immune cells
      (microglia, astrocytes) rather than representing core functions of full-length
      APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (microglia development) reflects downstream
      Abeta-mediated effects. Not a core function of APP itself. Keep as non-core.
    supported_by:
    - reference_id: PMID:22198949
      supporting_text: Microglia activated by extracellularly deposited amyloid β
        peptide (Aβ) act as a two-edged sword in Alzheimer's disease pathogenesis
- term:
    id: GO:0032760
    label: positive regulation of tumor necrosis factor production
  evidence_type: IGI
  original_reference_id: PMID:22198949
  review:
    summary: IGI annotation for positive regulation of tumor necrosis factor production.
      These immune/inflammatory effects are primarily mediated by Abeta cleavage products
      activating innate immune cells (microglia, astrocytes) rather than representing
      core functions of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (positive regulation of tumor necrosis
      factor production) reflects downstream Abeta-mediated effects. Not a core function
      of APP itself. Keep as non-core.
    supported_by:
    - reference_id: PMID:22198949
      supporting_text: they damage neurons by releasing neurotoxic proinflammatory
        mediators (M1 activation)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12054541
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:12054541
      supporting_text: A secreted form of human ADAM9 has an alpha-secretase activity
        for APP.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9774383
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:9774383
      supporting_text: Evidence that tumor necrosis factor alpha converting enzyme
        is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid
        protein precursor.
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:17112471
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:17112471
      supporting_text: ADAM19 is tightly associated with constitutive Alzheimer's
        disease APP alpha-secretase in A172 cells.
- term:
    id: GO:0050729
    label: positive regulation of inflammatory response
  evidence_type: IMP
  original_reference_id: PMID:29961672
  review:
    summary: IMP annotation for positive regulation of inflammatory response. These
      immune/inflammatory effects are primarily mediated by Abeta cleavage products
      activating innate immune cells (microglia, astrocytes) rather than representing
      core functions of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (positive regulation of inflammatory response)
      reflects downstream Abeta-mediated effects. Not a core function of APP itself.
      Keep as non-core.
    supported_by:
    - reference_id: PMID:29961672
      supporting_text: 2018 Dec 21. miR-15b reduces amyloid-β accumulation in SH-SY5Y
        cell line through targetting NF-κB signaling and BACE1.
- term:
    id: GO:1901224
    label: positive regulation of non-canonical NF-kappaB signal transduction
  evidence_type: IMP
  original_reference_id: PMID:29961672
  review:
    summary: IMP annotation for positive regulation of non-canonical NF-kappaB signal
      transduction. Abeta-mediated inflammatory signaling. Downstream effect.
    action: KEEP_AS_NON_CORE
    reason: NF-kappaB activation is a downstream inflammatory effect of Abeta. Keep
      as non-core.
    supported_by:
    - reference_id: PMID:29961672
      supporting_text: 2018 Dec 21. miR-15b reduces amyloid-β accumulation in SH-SY5Y
        cell line through targetting NF-κB signaling and BACE1.
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:29274751
  review:
    summary: IMP annotation for regulation of gene expression. Gene expression changes
      are downstream effects of APP processing and Abeta signaling. Some may be mediated
      by AICD transcriptional regulation (controversial). Not core APP function.
    action: KEEP_AS_NON_CORE
    reason: regulation of gene expression is a downstream effect. Keep as non-core.
    supported_by:
    - reference_id: PMID:29274751
      supporting_text: Reduced expression of Na(+)/Ca(2+) exchangers is associated
        with cognitive deficits seen in Alzheimer's disease model mice.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23973487
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:23973487
      supporting_text: Two β-strands of RAGE participate in the recognition and transport
        of amyloid-β peptide across the blood brain barrier.
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:26200696
  review:
    summary: IGI annotation for regulation of gene expression. Gene expression changes
      are downstream effects of APP processing and Abeta signaling. Some may be mediated
      by AICD transcriptional regulation (controversial). Not core APP function.
    action: KEEP_AS_NON_CORE
    reason: regulation of gene expression is a downstream effect. Keep as non-core.
    supported_by:
    - reference_id: PMID:26200696
      supporting_text: Dual pathways mediate β-amyloid stimulated glutathione release
        from astrocytes.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IDA
  original_reference_id: PMID:26006083
  review:
    summary: IDA annotation for positive regulation of gene expression. Gene expression
      changes are downstream effects of APP processing and Abeta signaling. Some may
      be mediated by AICD transcriptional regulation (controversial). Not core APP
      function.
    action: KEEP_AS_NON_CORE
    reason: positive regulation of gene expression is a downstream effect. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:26006083
      supporting_text: 2015 May 26. The multidrug resistance pump ABCB1 is a substrate
        for the ubiquitin ligase NEDD4-1.
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IDA
  original_reference_id: PMID:26006083
  review:
    summary: IDA annotation for negative regulation of gene expression. Gene expression
      changes are downstream effects of APP processing and Abeta signaling. Some may
      be mediated by AICD transcriptional regulation (controversial). Not core APP
      function.
    action: KEEP_AS_NON_CORE
    reason: negative regulation of gene expression is a downstream effect. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:26006083
      supporting_text: 2015 May 26. The multidrug resistance pump ABCB1 is a substrate
        for the ubiquitin ligase NEDD4-1.
- term:
    id: GO:0106003
    label: amyloid-beta complex
  evidence_type: TAS
  original_reference_id: PMID:22500019
  review:
    summary: TAS annotation based on author statement in referenced publication.
    action: ACCEPT
    reason: TAS annotation supported by literature.
    supported_by:
    - reference_id: PMID:22500019
      supporting_text: 2012 Apr 12. Amyloid β (Aβ) peptide directly activates amylin-3
        receptor subtype by triggering multiple intracellular signaling pathways.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:28164773
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:28164773
      supporting_text: Apolipoprotein E-mediated Modulation of ADAM10 in Alzheimer's
        Disease.
- term:
    id: GO:0001774
    label: microglial cell activation
  evidence_type: IGI
  original_reference_id: PMID:15457210
  review:
    summary: IGI annotation for microglial cell activation. These immune/inflammatory
      effects are primarily mediated by Abeta cleavage products activating innate
      immune cells (microglia, astrocytes) rather than representing core functions
      of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (microglial cell activation) reflects downstream
      Abeta-mediated effects. Not a core function of APP itself. Keep as non-core.
    supported_by:
    - reference_id: PMID:15457210
      supporting_text: RAGE is a cofactor for Abeta-induced neuronal perturbation
        in a model of Alzheimer's-type pathology
- term:
    id: GO:0001774
    label: microglial cell activation
  evidence_type: IGI
  original_reference_id: PMID:22406537
  review:
    summary: IGI annotation for microglial cell activation. These immune/inflammatory
      effects are primarily mediated by Abeta cleavage products activating innate
      immune cells (microglia, astrocytes) rather than representing core functions
      of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (microglial cell activation) reflects downstream
      Abeta-mediated effects. Not a core function of APP itself. Keep as non-core.
    supported_by:
    - reference_id: PMID:22406537
      supporting_text: A multimodal RAGE-specific inhibitor reduces amyloid β-mediated
        brain disorder in a mouse model of Alzheimer disease.
- term:
    id: GO:0048143
    label: astrocyte activation
  evidence_type: IGI
  original_reference_id: PMID:15457210
  review:
    summary: IGI annotation for astrocyte activation. These immune/inflammatory effects
      are primarily mediated by Abeta cleavage products activating innate immune cells
      (microglia, astrocytes) rather than representing core functions of full-length
      APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (astrocyte activation) reflects downstream
      Abeta-mediated effects. Not a core function of APP itself. Keep as non-core.
    supported_by:
    - reference_id: PMID:15457210
      supporting_text: RAGE is a cofactor for Abeta-induced neuronal perturbation
        in a model of Alzheimer's-type pathology
- term:
    id: GO:0032729
    label: positive regulation of type II interferon production
  evidence_type: IGI
  original_reference_id: PMID:17255335
  review:
    summary: IGI annotation for positive regulation of type II interferon production.
      These immune/inflammatory effects are primarily mediated by Abeta cleavage products
      activating innate immune cells (microglia, astrocytes) rather than representing
      core functions of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (positive regulation of type II interferon
      production) reflects downstream Abeta-mediated effects. Not a core function
      of APP itself. Keep as non-core.
    supported_by:
    - reference_id: PMID:17255335
      supporting_text: Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta
        plaque deposition and beta-secretase expression in Swedish mutant APP transgenic
        mice.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:28855300
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:28855300
      supporting_text: An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage
        site and affects shedding and phagocytic function.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:29061364
  review:
    summary: IGI annotation for positive regulation of gene expression. Gene expression
      changes are downstream effects of APP processing and Abeta signaling. Some may
      be mediated by AICD transcriptional regulation (controversial). Not core APP
      function.
    action: KEEP_AS_NON_CORE
    reason: positive regulation of gene expression is a downstream effect. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:29061364
      supporting_text: genotype-related increases in glycolysis, accompanied by increased
        PFKFB3, and an increase in the expression of ferritin
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:29061364
  review:
    summary: IGI annotation for negative regulation of gene expression. Gene expression
      changes are downstream effects of APP processing and Abeta signaling. Some may
      be mediated by AICD transcriptional regulation (controversial). Not core APP
      function.
    action: KEEP_AS_NON_CORE
    reason: negative regulation of gene expression is a downstream effect. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:29061364
      supporting_text: microglia prepared from wildtype mice and from transgenic mice
        that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1)
- term:
    id: GO:0032760
    label: positive regulation of tumor necrosis factor production
  evidence_type: IGI
  original_reference_id: PMID:29061364
  review:
    summary: IGI annotation for positive regulation of tumor necrosis factor production.
      These immune/inflammatory effects are primarily mediated by Abeta cleavage products
      activating innate immune cells (microglia, astrocytes) rather than representing
      core functions of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (positive regulation of tumor necrosis
      factor production) reflects downstream Abeta-mediated effects. Not a core function
      of APP itself. Keep as non-core.
    supported_by:
    - reference_id: PMID:29061364
      supporting_text: retention of iron in microglia increased TNFα expression
- term:
    id: GO:0045821
    label: positive regulation of glycolytic process
  evidence_type: IGI
  original_reference_id: PMID:29061364
  review:
    summary: IGI annotation for positive regulation of glycolytic process. Abeta-mediated
      metabolic effects in cells. Not a core function of APP.
    action: KEEP_AS_NON_CORE
    reason: Metabolic effects downstream of Abeta. Not core APP function. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:29061364
      supporting_text: increases in tumor necrosis factor-α (TNFα) and nitric oxide
        synthase 2 (NOS2) were accompanied by increased glycolysis
- term:
    id: GO:0070555
    label: response to interleukin-1
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28720718
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:28720718
      supporting_text: Phosphorylation of amyloid precursor protein by mutant LRRK2
        promotes AICD activity and neurotoxicity in Parkinson's disease.
- term:
    id: GO:1900272
    label: negative regulation of long-term synaptic potentiation
  evidence_type: IGI
  original_reference_id: PMID:16636059
  review:
    summary: 'IGI annotation based on genetic interaction evidence. NOTE: Many IGI
      annotations for APP involve Abeta-specific effects from transgenic mouse studies
      and may not represent full-length APP function.'
    action: ACCEPT
    reason: IGI annotation supported by genetic interaction data. Note potential cleavage
      product specificity.
    supported_by:
    - reference_id: PMID:16636059
      supporting_text: 2006 Apr 24. Neprilysin-sensitive synapse-associated amyloid-beta
        peptide oligomers impair neuronal plasticity and cognitive function.
- term:
    id: GO:0032722
    label: positive regulation of chemokine production
  evidence_type: IGI
  original_reference_id: PMID:22406537
  review:
    summary: IGI annotation for positive regulation of chemokine production. These
      immune/inflammatory effects are primarily mediated by Abeta cleavage products
      activating innate immune cells (microglia, astrocytes) rather than representing
      core functions of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (positive regulation of chemokine production)
      reflects downstream Abeta-mediated effects. Not a core function of APP itself.
      Keep as non-core.
    supported_by:
    - reference_id: PMID:22406537
      supporting_text: In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited
        β-secretase activity and Aβ production and suppressed microglia activation
        and the neuroinflammatory response
- term:
    id: GO:0032731
    label: positive regulation of interleukin-1 beta production
  evidence_type: IGI
  original_reference_id: PMID:22406537
  review:
    summary: IGI annotation for positive regulation of interleukin-1 beta production.
      These immune/inflammatory effects are primarily mediated by Abeta cleavage products
      activating innate immune cells (microglia, astrocytes) rather than representing
      core functions of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (positive regulation of interleukin-1 beta
      production) reflects downstream Abeta-mediated effects. Not a core function
      of APP itself. Keep as non-core.
    supported_by:
    - reference_id: PMID:22406537
      supporting_text: Receptor for advanced glycation end products (RAGE) mediates
        Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD
- term:
    id: GO:0032755
    label: positive regulation of interleukin-6 production
  evidence_type: IGI
  original_reference_id: PMID:22406537
  review:
    summary: IGI annotation for positive regulation of interleukin-6 production. These
      immune/inflammatory effects are primarily mediated by Abeta cleavage products
      activating innate immune cells (microglia, astrocytes) rather than representing
      core functions of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (positive regulation of interleukin-6 production)
      reflects downstream Abeta-mediated effects. Not a core function of APP itself.
      Keep as non-core.
    supported_by:
    - reference_id: PMID:22406537
      supporting_text: Receptor for advanced glycation end products (RAGE) mediates
        Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD
- term:
    id: GO:0032760
    label: positive regulation of tumor necrosis factor production
  evidence_type: IGI
  original_reference_id: PMID:22406537
  review:
    summary: IGI annotation for positive regulation of tumor necrosis factor production.
      These immune/inflammatory effects are primarily mediated by Abeta cleavage products
      activating innate immune cells (microglia, astrocytes) rather than representing
      core functions of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (positive regulation of tumor necrosis
      factor production) reflects downstream Abeta-mediated effects. Not a core function
      of APP itself. Keep as non-core.
    supported_by:
    - reference_id: PMID:22406537
      supporting_text: Receptor for advanced glycation end products (RAGE) mediates
        Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD
- term:
    id: GO:0032760
    label: positive regulation of tumor necrosis factor production
  evidence_type: IGI
  original_reference_id: PMID:12808450
  review:
    summary: IGI annotation for positive regulation of tumor necrosis factor production.
      These immune/inflammatory effects are primarily mediated by Abeta cleavage products
      activating innate immune cells (microglia, astrocytes) rather than representing
      core functions of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (positive regulation of tumor necrosis
      factor production) reflects downstream Abeta-mediated effects. Not a core function
      of APP itself. Keep as non-core.
    supported_by:
    - reference_id: PMID:12808450
      supporting_text: RAGE mediates amyloid-beta peptide transport across the blood-brain
        barrier and accumulation in brain.
- term:
    id: GO:1903523
    label: negative regulation of blood circulation
  evidence_type: IGI
  original_reference_id: PMID:12808450
  review:
    summary: IGI annotation for negative regulation of blood circulation. Vascular
      effects of Abeta peptides including vasoconstriction and endothelin production.
      These are pathological consequences of Abeta accumulation rather than core APP
      functions.
    action: KEEP_AS_NON_CORE
    reason: Vascular annotation (negative regulation of blood circulation) is a downstream
      Abeta-mediated pathological effect. Keep as non-core.
    supported_by:
    - reference_id: PMID:12808450
      supporting_text: RAGE mediates amyloid-beta peptide transport across the blood-brain
        barrier and accumulation in brain.
- term:
    id: GO:1904472
    label: positive regulation of endothelin production
  evidence_type: IGI
  original_reference_id: PMID:12808450
  review:
    summary: IGI annotation for positive regulation of endothelin production. Vascular
      effects of Abeta peptides including vasoconstriction and endothelin production.
      These are pathological consequences of Abeta accumulation rather than core APP
      functions.
    action: KEEP_AS_NON_CORE
    reason: Vascular annotation (positive regulation of endothelin production) is
      a downstream Abeta-mediated pathological effect. Keep as non-core.
    supported_by:
    - reference_id: PMID:12808450
      supporting_text: RAGE mediates amyloid-beta peptide transport across the blood-brain
        barrier and accumulation in brain.
- term:
    id: GO:0050786
    label: RAGE receptor binding
  evidence_type: IPI
  original_reference_id: PMID:22406537
  isoform: P05067-PRO_0000000093
  review:
    summary: IPI annotation for Abeta-RAGE binding. Deane et al. (2012) showed a RAGE
      inhibitor (FPS-ZM1) blocks Abeta binding to the V domain of RAGE, preventing
      Abeta-induced cellular stress. This is a core molecular interaction of Abeta.
    action: ACCEPT
    reason: Well-documented Abeta-RAGE interaction. Annotation correctly applies to
      Abeta cleavage product. RAGE binding is key to Abeta neurotoxicity mechanism.
    supported_by:
    - reference_id: PMID:22406537
      supporting_text: we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1)
        that blocked Abeta binding to the V domain of RAGE
- term:
    id: GO:1901224
    label: positive regulation of non-canonical NF-kappaB signal transduction
  evidence_type: IDA
  original_reference_id: PMID:22406537
  review:
    summary: IDA annotation for positive regulation of non-canonical NF-kappaB signal
      transduction. Abeta-mediated inflammatory signaling. Downstream effect.
    action: KEEP_AS_NON_CORE
    reason: NF-kappaB activation is a downstream inflammatory effect of Abeta. Keep
      as non-core.
    supported_by:
    - reference_id: PMID:22406537
      supporting_text: Receptor for advanced glycation end products (RAGE) mediates
        Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD
- term:
    id: GO:0005798
    label: Golgi-associated vesicle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0055037
    label: recycling endosome
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:23525105
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:23525105
      supporting_text: 2013 Mar 22. Transcriptional regulation of insulin-degrading
        enzyme modulates mitochondrial amyloid β (Aβ) peptide catabolism and functionality.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0050890
    label: cognition
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for cognition. Downstream behavioral phenotype of APP/Abeta
      biology. Not a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: Cognition is a high-level phenotype downstream of APP biology. Keep as
      non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9617595
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:23106396
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:23106396
      supporting_text: Amyloid-β oligomers are sequestered by both intracellular and
        extracellular chaperones.
- term:
    id: GO:0106003
    label: amyloid-beta complex
  evidence_type: IPI
  original_reference_id: PMID:22179788
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:22179788
      supporting_text: The extracellular chaperone clusterin sequesters oligomeric
        forms of the amyloid-β(1-40) peptide.
- term:
    id: GO:0031904
    label: endosome lumen
  evidence_type: TAS
  original_reference_id: PMID:24305806
  review:
    summary: TAS annotation based on author statement in referenced publication.
    action: ACCEPT
    reason: TAS annotation supported by literature.
    supported_by:
    - reference_id: PMID:24305806
      supporting_text: Pharmacologic inhibition of ROCK2 suppresses amyloid-β production
        in an Alzheimer's disease mouse model.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:27853422
  review:
    summary: IGI annotation for positive regulation of gene expression. Gene expression
      changes are downstream effects of APP processing and Abeta signaling. Some may
      be mediated by AICD transcriptional regulation (controversial). Not core APP
      function.
    action: KEEP_AS_NON_CORE
    reason: positive regulation of gene expression is a downstream effect. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:27853422
      supporting_text: eCollection 2016. ROCK1 Is Associated with Alzheimer's Disease-Specific
        Plaques, as well as Enhances Autophagosome Formation But not Autophagic Aβ
        Clearance.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:27853422
  review:
    summary: IMP annotation for positive regulation of gene expression. Gene expression
      changes are downstream effects of APP processing and Abeta signaling. Some may
      be mediated by AICD transcriptional regulation (controversial). Not core APP
      function.
    action: KEEP_AS_NON_CORE
    reason: positive regulation of gene expression is a downstream effect. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:27853422
      supporting_text: eCollection 2016. ROCK1 Is Associated with Alzheimer's Disease-Specific
        Plaques, as well as Enhances Autophagosome Formation But not Autophagic Aβ
        Clearance.
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:27853422
  review:
    summary: IGI annotation for negative regulation of gene expression. Gene expression
      changes are downstream effects of APP processing and Abeta signaling. Some may
      be mediated by AICD transcriptional regulation (controversial). Not core APP
      function.
    action: KEEP_AS_NON_CORE
    reason: negative regulation of gene expression is a downstream effect. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:27853422
      supporting_text: eCollection 2016. ROCK1 Is Associated with Alzheimer's Disease-Specific
        Plaques, as well as Enhances Autophagosome Formation But not Autophagic Aβ
        Clearance.
- term:
    id: GO:0007611
    label: learning or memory
  evidence_type: IMP
  original_reference_id: PMID:15457210
  review:
    summary: IMP annotation for learning or memory. APP and its cleavage products
      (especially Abeta oligomers) affect learning and memory, but this is a downstream
      phenotypic consequence of APP processing rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: learning or memory is a downstream consequence of APP/Abeta biology. Important
      for disease relevance but not a core function. Keep as non-core.
    supported_by:
    - reference_id: PMID:15457210
      supporting_text: Double Tgs (mutant APP (mAPP)/RAGE) displayed early abnormalities
        in spatial learning/memory, accompanied by altered activation of markers of
        synaptic plasticity and exaggerated neuropathologic findings, before such
        changes were found in mAPP mice
- term:
    id: GO:0007611
    label: learning or memory
  evidence_type: IGI
  original_reference_id: PMID:15457210
  review:
    summary: IGI annotation for learning or memory. APP and its cleavage products
      (especially Abeta oligomers) affect learning and memory, but this is a downstream
      phenotypic consequence of APP processing rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: learning or memory is a downstream consequence of APP/Abeta biology. Important
      for disease relevance but not a core function. Keep as non-core.
    supported_by:
    - reference_id: PMID:15457210
      supporting_text: Tg mice bearing a dominant-negative RAGE construct targeted
        to neurons crossed with mAPP animals displayed preservation of spatial learning/memory
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: NAS
  original_reference_id: PMID:15457210
  review:
    summary: RAGE functions as a cell surface receptor for Abeta.
    action: ACCEPT
    reason: Paper describes RAGE as signal-transducing cell surface acceptor for Abeta.
    supported_by:
    - reference_id: PMID:15457210
      supporting_text: Receptor for Advanced Glycation Endproducts (RAGE), a multiligand
        receptor in the immunoglobulin superfamily, functions as a signal-transducing
        cell surface acceptor for amyloid-beta peptide (Abeta)
- term:
    id: GO:0070374
    label: positive regulation of ERK1 and ERK2 cascade
  evidence_type: IGI
  original_reference_id: PMID:15457210
  review:
    summary: IGI annotation for positive regulation of ERK1 and ERK2 cascade. Abeta
      activates MAPK/ERK signaling in various cell types. Downstream signaling effect,
      not core APP function.
    action: KEEP_AS_NON_CORE
    reason: ERK cascade activation is a downstream effect of Abeta. Keep as non-core.
    supported_by:
    - reference_id: PMID:15457210
      supporting_text: Receptor for Advanced Glycation Endproducts (RAGE), a multiligand
        receptor in the immunoglobulin superfamily, functions as a signal-transducing
        cell surface acceptor for amyloid-beta peptide (Abeta)
- term:
    id: GO:1990535
    label: neuron projection maintenance
  evidence_type: IGI
  original_reference_id: PMID:20445063
  review:
    summary: 'IGI annotation based on genetic interaction evidence. NOTE: Many IGI
      annotations for APP involve Abeta-specific effects from transgenic mouse studies
      and may not represent full-length APP function.'
    action: ACCEPT
    reason: IGI annotation supported by genetic interaction data. Note potential cleavage
      product specificity.
    supported_by:
    - reference_id: PMID:20445063
      supporting_text: Memory impairment in transgenic Alzheimer mice requires cellular
        prion protein.
- term:
    id: GO:0007611
    label: learning or memory
  evidence_type: IGI
  original_reference_id: PMID:24052308
  review:
    summary: IGI annotation for learning or memory. APP and its cleavage products
      (especially Abeta oligomers) affect learning and memory, but this is a downstream
      phenotypic consequence of APP processing rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: learning or memory is a downstream consequence of APP/Abeta biology. Important
      for disease relevance but not a core function. Keep as non-core.
    supported_by:
    - reference_id: PMID:24052308
      supporting_text: Human LilrB2 is a β-amyloid receptor and its murine homolog
        PirB regulates synaptic plasticity in an Alzheimer's model.
- term:
    id: GO:0005178
    label: integrin binding
  evidence_type: IDA
  original_reference_id: PMID:21126803
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:21126803
      supporting_text: Perlecan domain V inhibits α2 integrin-mediated amyloid-β neurotoxicity.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IMP
  original_reference_id: PMID:23640054
  review:
    summary: IMP annotation based on mutant phenotype analysis.
    action: ACCEPT
    reason: IMP annotation supported by mutant phenotype data.
    supported_by:
    - reference_id: PMID:23640054
      supporting_text: Brain interstitial oligomeric amyloid β increases with age
        and is resistant to clearance from brain in a mouse model of Alzheimer's disease.
- term:
    id: GO:0106003
    label: amyloid-beta complex
  evidence_type: IMP
  original_reference_id: PMID:23640054
  review:
    summary: IMP annotation based on mutant phenotype analysis.
    action: ACCEPT
    reason: IMP annotation supported by mutant phenotype data.
    supported_by:
    - reference_id: PMID:23640054
      supporting_text: Brain interstitial oligomeric amyloid β increases with age
        and is resistant to clearance from brain in a mouse model of Alzheimer's disease.
- term:
    id: GO:0050750
    label: low-density lipoprotein particle receptor binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: IDA
  original_reference_id: PMID:17251419
  negated: true
  review:
    summary: NOT annotation - Lacor et al. (2007) showed Abeta oligomers (ADDLs) bind
      to dendritic spines, not dendrite shafts. The annotation indicates where full-length
      APP or its products are NOT found. This study focused on Abeta oligomer binding
      specificity to excitatory pyramidal neurons.
    action: ACCEPT
    reason: The negated annotation accurately captures the spatial specificity of
      Abeta/ADDL binding shown in PMID:17251419.
    supported_by:
    - reference_id: PMID:17251419
      supporting_text: ADDLs bound to neurons with specificity, attaching to presumed
        excitatory pyramidal neurons but not GABAergic neurons... consistent with
        observed attachment of ADDLs to dendritic spines.
- term:
    id: GO:0032590
    label: dendrite membrane
  evidence_type: TAS
  original_reference_id: PMID:20032460
  negated: true
  review:
    summary: NOT annotation - Zhao et al. (2010) showed that Abeta oligomers (ADDLs)
      bind specifically to dendritic spines expressing surface AMPA receptors (particularly
      GluR2), not the general dendrite membrane. The specificity is for postsynaptic
      compartments.
    action: ACCEPT
    reason: The negated annotation accurately reflects the spatial selectivity of
      ADDL binding shown in PMID:20032460.
    supported_by:
    - reference_id: PMID:20032460
      supporting_text: ADDL binding occurs in dendritic spines that express surface
        AMPA receptors, particularly the calcium-impermeable type II AMPA receptor
        subunit (GluR2).
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9010034
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9010034
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9010091
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0031904
    label: endosome lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5692495
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0031904
    label: endosome lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9010096
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:23921129
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:23921129
      supporting_text: soluble Aβ oligomers interact with FcγRIIb in vitro and in
        AD brains
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IGI
  original_reference_id: PMID:23921129
  review:
    summary: IGI annotation for positive regulation of transcription by RNA polymerase
      II. AICD has been reported to regulate transcription through Fe65/Tip60 complex,
      but this remains controversial and applies to a cleavage product rather than
      full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Transcriptional regulation by AICD is controversial and represents a cleavage
      product function. Keep as non-core.
    supported_by:
    - reference_id: PMID:23921129
      supporting_text: FcγRIIb is significantly upregulated in the hippocampus of
        AD brains and neuronal cells exposed to synthetic Aβ
- term:
    id: GO:0007611
    label: learning or memory
  evidence_type: IGI
  original_reference_id: PMID:21113149
  review:
    summary: IGI annotation for learning or memory. APP and its cleavage products
      (especially Abeta oligomers) affect learning and memory, but this is a downstream
      phenotypic consequence of APP processing rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: learning or memory is a downstream consequence of APP/Abeta biology. Important
      for disease relevance but not a core function. Keep as non-core.
    supported_by:
    - reference_id: PMID:21113149
      supporting_text: Reversing EphB2 depletion rescues cognitive functions in Alzheimer
        model.
- term:
    id: GO:0097645
    label: amylin binding
  evidence_type: TAS
  original_reference_id: PMID:22500019
  review:
    summary: TAS annotation based on author statement in referenced publication.
    action: ACCEPT
    reason: TAS annotation supported by literature.
    supported_by:
    - reference_id: PMID:22500019
      supporting_text: 2012 Apr 12. Amyloid β (Aβ) peptide directly activates amylin-3
        receptor subtype by triggering multiple intracellular signaling pathways.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:22198949
  review:
    summary: IGI annotation for positive regulation of gene expression. Gene expression
      changes are downstream effects of APP processing and Abeta signaling. Some may
      be mediated by AICD transcriptional regulation (controversial). Not core APP
      function.
    action: KEEP_AS_NON_CORE
    reason: positive regulation of gene expression is a downstream effect. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:22198949
      supporting_text: TLR2-mediated Aβ42-triggered inflammatory activation
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:22198949
  review:
    summary: IGI annotation for negative regulation of gene expression. Gene expression
      changes are downstream effects of APP processing and Abeta signaling. Some may
      be mediated by AICD transcriptional regulation (controversial). Not core APP
      function.
    action: KEEP_AS_NON_CORE
    reason: negative regulation of gene expression is a downstream effect. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:22198949
      supporting_text: TLR2 deficiency in microglia shifts M1- to M2-inflammatory
        activation in vivo
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IDA
  original_reference_id: PMID:26005850
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:26005850
      supporting_text: guided Aβ trafficking to Rab5 and Rab11
- term:
    id: GO:0070381
    label: endosome to plasma membrane transport vesicle
  evidence_type: IDA
  original_reference_id: PMID:26005850
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:26005850
      supporting_text: leading to Aβ endothelial transcytosis and clearance
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:26005850
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:26005850
      supporting_text: Aβ clearance across the murine blood-brain barrier (BBB)
- term:
    id: GO:0048143
    label: astrocyte activation
  evidence_type: IGI
  original_reference_id: PMID:20445063
  review:
    summary: IGI annotation for astrocyte activation. These immune/inflammatory effects
      are primarily mediated by Abeta cleavage products activating innate immune cells
      (microglia, astrocytes) rather than representing core functions of full-length
      APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (astrocyte activation) reflects downstream
      Abeta-mediated effects. Not a core function of APP itself. Keep as non-core.
    supported_by:
    - reference_id: PMID:20445063
      supporting_text: Memory impairment in transgenic Alzheimer mice requires cellular
        prion protein.
- term:
    id: GO:0005109
    label: frizzled binding
  evidence_type: IPI
  original_reference_id: PMID:18234671
  review:
    summary: Abeta binds to the Frizzled cysteine-rich domain at or near the Wnt-binding
      site.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:18234671
      supporting_text: Abeta binds to the Fz cysteine-rich domain at or in close proximity
        to the Wnt-binding site and inhibits the canonical Wnt signaling pathway
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IGI
  original_reference_id: PMID:18234671
  review:
    summary: IGI annotation for negative regulation of gene expression. Gene expression
      changes are downstream effects of APP processing and Abeta signaling. Some may
      be mediated by AICD transcriptional regulation (controversial). Not core APP
      function.
    action: KEEP_AS_NON_CORE
    reason: negative regulation of gene expression is a downstream effect. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:18234671
      supporting_text: Amyloid-beta binds to the extracellular cysteine-rich domain
        of Frizzled and inhibits Wnt/beta-catenin signaling
- term:
    id: GO:0090090
    label: negative regulation of canonical Wnt signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:18234671
  review:
    summary: IDA annotation for negative regulation of canonical Wnt signaling pathway.
      APP/Abeta interaction with Wnt signaling components. Not core function.
    action: KEEP_AS_NON_CORE
    reason: Wnt signaling regulation is not a core function of APP. Keep as non-core.
    supported_by:
    - reference_id: PMID:18234671
      supporting_text: Abeta binds to the Fz cysteine-rich domain at or in close proximity
        to the Wnt-binding site and inhibits the canonical Wnt signaling pathway
- term:
    id: GO:1900181
    label: negative regulation of protein localization to nucleus
  evidence_type: IGI
  original_reference_id: PMID:18234671
  review:
    summary: By inhibiting Wnt signaling, Abeta prevents beta-catenin nuclear localization
      required for Wnt target gene activation.
    action: ACCEPT
    reason: IGI annotation reflects Abeta blocking beta-catenin nuclear translocation
      by inhibiting Wnt signaling.
    supported_by:
    - reference_id: PMID:18234671
      supporting_text: Amyloid-beta binds to the extracellular cysteine-rich domain
        of Frizzled and inhibits Wnt/beta-catenin signaling
- term:
    id: GO:0002265
    label: astrocyte activation involved in immune response
  evidence_type: IGI
  original_reference_id: PMID:23152628
  review:
    summary: IGI annotation for astrocyte activation involved in immune response.
      These immune/inflammatory effects are primarily mediated by Abeta cleavage products
      activating innate immune cells (microglia, astrocytes) rather than representing
      core functions of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (astrocyte activation involved in immune
      response) reflects downstream Abeta-mediated effects. Not a core function of
      APP itself. Keep as non-core.
    supported_by:
    - reference_id: PMID:23152628
      supporting_text: LRP1 in brain vascular smooth muscle cells mediates local clearance
        of Alzheimer's amyloid-β.
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:23152628
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:23152628
      supporting_text: LRP1 in brain vascular smooth muscle cells mediates local clearance
        of Alzheimer's amyloid-β.
- term:
    id: GO:0043395
    label: heparan sulfate proteoglycan binding
  evidence_type: IMP
  original_reference_id: PMID:21289173
  review:
    summary: IMP annotation based on mutant phenotype analysis.
    action: ACCEPT
    reason: IMP annotation supported by mutant phenotype data.
    supported_by:
    - reference_id: PMID:21289173
      supporting_text: Heparan sulphate proteoglycan and the low-density lipoprotein
        receptor-related protein 1 constitute major pathways for neuronal amyloid-beta
        uptake.
- term:
    id: GO:1904399
    label: heparan sulfate binding
  evidence_type: TAS
  original_reference_id: PMID:21289173
  review:
    summary: TAS annotation based on author statement in referenced publication.
    action: ACCEPT
    reason: TAS annotation supported by literature.
    supported_by:
    - reference_id: PMID:21289173
      supporting_text: Heparan sulphate proteoglycan and the low-density lipoprotein
        receptor-related protein 1 constitute major pathways for neuronal amyloid-beta
        uptake.
- term:
    id: GO:1904646
    label: cellular response to amyloid-beta
  evidence_type: IGI
  original_reference_id: PMID:23152628
  review:
    summary: 'IGI annotation based on genetic interaction evidence. NOTE: Many IGI
      annotations for APP involve Abeta-specific effects from transgenic mouse studies
      and may not represent full-length APP function.'
    action: ACCEPT
    reason: IGI annotation supported by genetic interaction data. Note potential cleavage
      product specificity.
    supported_by:
    - reference_id: PMID:23152628
      supporting_text: LRP1 in brain vascular smooth muscle cells mediates local clearance
        of Alzheimer's amyloid-β.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:9228033
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:9228033
      supporting_text: Interaction of apolipoprotein J-amyloid beta-peptide complex
        with low density lipoprotein receptor-related protein-2/megalin.
- term:
    id: GO:0034185
    label: apolipoprotein binding
  evidence_type: IPI
  original_reference_id: PMID:22138302
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:22138302
      supporting_text: Preferential interactions between ApoE-containing lipoproteins
        and Aβ revealed by a detection method that combines size exclusion chromatography
        with non-reducing gel-shift.
- term:
    id: GO:0034363
    label: intermediate-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:22138302
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:22138302
      supporting_text: Preferential interactions between ApoE-containing lipoproteins
        and Aβ revealed by a detection method that combines size exclusion chromatography
        with non-reducing gel-shift.
- term:
    id: GO:0034364
    label: high-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:22138302
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:22138302
      supporting_text: Preferential interactions between ApoE-containing lipoproteins
        and Aβ revealed by a detection method that combines size exclusion chromatography
        with non-reducing gel-shift.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:9228033
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:9228033
      supporting_text: Interaction of apolipoprotein J-amyloid beta-peptide complex
        with low density lipoprotein receptor-related protein-2/megalin.
- term:
    id: GO:1990777
    label: lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:22138302
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:22138302
      supporting_text: Preferential interactions between ApoE-containing lipoproteins
        and Aβ revealed by a detection method that combines size exclusion chromatography
        with non-reducing gel-shift.
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:23164821
  review:
    summary: IMP annotation for positive regulation of gene expression. Gene expression
      changes are downstream effects of APP processing and Abeta signaling. Some may
      be mediated by AICD transcriptional regulation (controversial). Not core APP
      function.
    action: KEEP_AS_NON_CORE
    reason: positive regulation of gene expression is a downstream effect. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:23164821
      supporting_text: Aβ induction of DKK1 and all five of the common genes, including
        EGR1, NAB2 and KLF10, was significantly blocked by the silencing of CLU
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: IDA
  original_reference_id: PMID:22944668
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:22944668
      supporting_text: 'Antimicrobial activity of human islet amyloid polypeptides:
        an insight into amyloid peptides'' connection with antimicrobial peptides.'
- term:
    id: GO:0034185
    label: apolipoprotein binding
  evidence_type: IPI
  original_reference_id: PMID:9211985
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:9211985
      supporting_text: These binding studies provide one possible explanation for
        protective effects of both apoE2 and E3 against the development of Alzheimer's
        disease
- term:
    id: GO:0042157
    label: lipoprotein metabolic process
  evidence_type: IC
  original_reference_id: PMID:9211985
  review:
    summary: IC annotation inferred by curator based on available evidence.
    action: ACCEPT
    reason: IC annotation supported by curator judgment.
    supported_by:
    - reference_id: PMID:9211985
      supporting_text: In humans, apolipoprotein E (apoE) has three major isoforms
- term:
    id: GO:0098815
    label: modulation of excitatory postsynaptic potential
  evidence_type: IGI
  original_reference_id: PMID:20974225
  review:
    summary: 'IGI annotation based on genetic interaction evidence. NOTE: Many IGI
      annotations for APP involve Abeta-specific effects from transgenic mouse studies
      and may not represent full-length APP function.'
    action: ACCEPT
    reason: IGI annotation supported by genetic interaction data. Note potential cleavage
      product specificity.
    supported_by:
    - reference_id: PMID:20974225
      supporting_text: Epub 2010 Oct 23. Activation of nicotinic α(7) acetylcholine
        receptor enhances long term potentation in wild type mice but not in APP(swe)/PS1ΔE9
        mice.
- term:
    id: GO:1900273
    label: positive regulation of long-term synaptic potentiation
  evidence_type: IGI
  original_reference_id: PMID:20974225
  review:
    summary: 'IGI annotation based on genetic interaction evidence. NOTE: Many IGI
      annotations for APP involve Abeta-specific effects from transgenic mouse studies
      and may not represent full-length APP function.'
    action: ACCEPT
    reason: IGI annotation supported by genetic interaction data. Note potential cleavage
      product specificity.
    supported_by:
    - reference_id: PMID:20974225
      supporting_text: Epub 2010 Oct 23. Activation of nicotinic α(7) acetylcholine
        receptor enhances long term potentation in wild type mice but not in APP(swe)/PS1ΔE9
        mice.
- term:
    id: GO:0097060
    label: synaptic membrane
  evidence_type: IDA
  original_reference_id: PMID:17308309
  negated: true
  review:
    summary: NOT annotation - De Felice et al. (2007) showed Abeta oligomers (ADDLs)
      bind specifically at or near NMDA receptors, not the general synaptic membrane.
      The study showed ADDLs co-immunoprecipitate with NMDA-R subunits and require
      NMDA-R activation for their effects.
    action: ACCEPT
    reason: The negated annotation accurately captures the receptor-specific binding
      of ADDLs shown in PMID:17308309, distinguishing binding specificity from general
      synaptic membrane localization.
    supported_by:
    - reference_id: PMID:17308309
      supporting_text: ADDLs that were bound to detergent-extracted synaptosomal membranes
        co-immunoprecipitated with NMDA-R subunits... ADDLs bind to or in close proximity
        to NMDA-Rs, triggering neuronal damage through NMDA-R-dependent calcium flux.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IPI
  original_reference_id: PMID:18568035
  isoform: P05067-PRO_0000000093
  review:
    summary: IPI annotation for Abeta complex formation. Shankar et al. (2008) showed
      that Abeta dimers (Abeta42-Abeta40 complexes) are the minimal synaptotoxic species.
      The IPI annotation correctly captures that Abeta42 forms complexes with Abeta40.
    action: ACCEPT
    reason: Well-supported IPI annotation correctly targeting Abeta cleavage product.
      Dimerization is essential for synaptotoxicity.
    supported_by:
    - reference_id: PMID:18568035
      supporting_text: These various effects were specifically attributable to Abeta
        dimers
- term:
    id: GO:0061844
    label: antimicrobial humoral immune response mediated by antimicrobial peptide
  evidence_type: IMP
  original_reference_id: PMID:20209079
  review:
    summary: IMP annotation for antimicrobial humoral immune response mediated by
      antimicrobial peptide. These immune/inflammatory effects are primarily mediated
      by Abeta cleavage products activating innate immune cells (microglia, astrocytes)
      rather than representing core functions of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (antimicrobial humoral immune response
      mediated by antimicrobial peptide) reflects downstream Abeta-mediated effects.
      Not a core function of APP itself. Keep as non-core.
    supported_by:
    - reference_id: PMID:20209079
      supporting_text: Abeta exerts antimicrobial activity against eight common and
        clinically relevant microorganisms with a potency equivalent to, and in some
        cases greater than, LL-37
- term:
    id: GO:0046982
    label: protein heterodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:18568035
  isoform: P05067-PRO_0000000093
  review:
    summary: IPI annotation for Abeta heterodimerization. GOA shows Abeta42 (PRO_0000000093)
      heterodimerizes with Abeta40 (PRO_0000000092). Shankar et al. (2008) demonstrated
      that Abeta dimers are the smallest synaptotoxic species.
    action: ACCEPT
    reason: Well-supported IPI annotation correctly targeting Abeta42. The Abeta42-Abeta40
      heterodimer is the pathogenic species.
    supported_by:
    - reference_id: PMID:18568035
      supporting_text: These various effects were specifically attributable to Abeta
        dimers
- term:
    id: GO:0051247
    label: positive regulation of protein metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:20164328
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:20164328
      supporting_text: Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer
        accumulation, exacerbating early-stage cognitive decline and septohippocampal
        pathology in a mouse model of Alzheimer's disease.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952289
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0007611
    label: learning or memory
  evidence_type: IGI
  original_reference_id: PMID:19587288
  review:
    summary: IGI annotation for learning or memory. APP and its cleavage products
      (especially Abeta oligomers) affect learning and memory, but this is a downstream
      phenotypic consequence of APP processing rather than a core molecular function.
    action: KEEP_AS_NON_CORE
    reason: learning or memory is a downstream consequence of APP/Abeta biology. Important
      for disease relevance but not a core function. Keep as non-core.
    supported_by:
    - reference_id: PMID:19587288
      supporting_text: Deletion of the alpha 7 nicotinic acetylcholine receptor gene
        improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's
        disease.
- term:
    id: GO:0050808
    label: synapse organization
  evidence_type: IGI
  original_reference_id: PMID:19587288
  review:
    summary: 'IGI annotation based on genetic interaction evidence. NOTE: Many IGI
      annotations for APP involve Abeta-specific effects from transgenic mouse studies
      and may not represent full-length APP function.'
    action: ACCEPT
    reason: IGI annotation supported by genetic interaction data. Note potential cleavage
      product specificity.
    supported_by:
    - reference_id: PMID:19587288
      supporting_text: Deletion of the alpha 7 nicotinic acetylcholine receptor gene
        improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's
        disease.
- term:
    id: GO:0005796
    label: Golgi lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871506
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:1990000
    label: amyloid fibril formation
  evidence_type: IMP
  original_reference_id: PMID:25620700
  review:
    summary: IMP annotation based on mutant phenotype analysis.
    action: ACCEPT
    reason: IMP annotation supported by mutant phenotype data.
    supported_by:
    - reference_id: PMID:25620700
      supporting_text: 2015 Jan 22. A genome-wide gene-expression analysis and database
        in transgenic mice during development of amyloid or tau pathology.
- term:
    id: GO:0001878
    label: response to yeast
  evidence_type: IMP
  original_reference_id: PMID:20209079
  review:
    summary: IMP annotation for response to yeast. These immune/inflammatory effects
      are primarily mediated by Abeta cleavage products activating innate immune cells
      (microglia, astrocytes) rather than representing core functions of full-length
      APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (response to yeast) reflects downstream
      Abeta-mediated effects. Not a core function of APP itself. Keep as non-core.
    supported_by:
    - reference_id: PMID:20209079
      supporting_text: anti-Abeta immunoreactive material in AD whole brain homogenates
        is active against Candida albicans, the pathogen we identified as most sensitive
        to synthetic Abeta
- term:
    id: GO:0019731
    label: antibacterial humoral response
  evidence_type: IDA
  original_reference_id: PMID:20209079
  review:
    summary: IDA annotation for antibacterial humoral response. These immune/inflammatory
      effects are primarily mediated by Abeta cleavage products activating innate
      immune cells (microglia, astrocytes) rather than representing core functions
      of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (antibacterial humoral response) reflects
      downstream Abeta-mediated effects. Not a core function of APP itself. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:20209079
      supporting_text: Abeta exerts antimicrobial activity against eight common and
        clinically relevant microorganisms with a potency equivalent to, and in some
        cases greater than, LL-37
- term:
    id: GO:0019732
    label: antifungal humoral response
  evidence_type: IMP
  original_reference_id: PMID:20209079
  review:
    summary: IMP annotation for antifungal humoral response. These immune/inflammatory
      effects are primarily mediated by Abeta cleavage products activating innate
      immune cells (microglia, astrocytes) rather than representing core functions
      of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (antifungal humoral response) reflects
      downstream Abeta-mediated effects. Not a core function of APP itself. Keep as
      non-core.
    supported_by:
    - reference_id: PMID:20209079
      supporting_text: anti-Abeta immunoreactive material in AD whole brain homogenates
        is active against Candida albicans, the pathogen we identified as most sensitive
        to synthetic Abeta
- term:
    id: GO:0045087
    label: innate immune response
  evidence_type: IMP
  original_reference_id: PMID:20209079
  review:
    summary: IMP annotation for innate immune response. These immune/inflammatory
      effects are primarily mediated by Abeta cleavage products activating innate
      immune cells (microglia, astrocytes) rather than representing core functions
      of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (innate immune response) reflects downstream
      Abeta-mediated effects. Not a core function of APP itself. Keep as non-core.
    supported_by:
    - reference_id: PMID:20209079
      supporting_text: Our findings suggest Abeta is a hitherto unrecognized AMP that
        may normally function in the innate immune system
- term:
    id: GO:0050829
    label: defense response to Gram-negative bacterium
  evidence_type: IDA
  original_reference_id: PMID:20209079
  review:
    summary: IDA annotation for defense response to Gram-negative bacterium. These
      immune/inflammatory effects are primarily mediated by Abeta cleavage products
      activating innate immune cells (microglia, astrocytes) rather than representing
      core functions of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (defense response to Gram-negative bacterium)
      reflects downstream Abeta-mediated effects. Not a core function of APP itself.
      Keep as non-core.
    supported_by:
    - reference_id: PMID:20209079
      supporting_text: The synthetic Abeta peptides demonstrated antibiotic activity
        against Gram-negative and Gram-positive bacteria and the yeast C. albicans
- term:
    id: GO:0050830
    label: defense response to Gram-positive bacterium
  evidence_type: IDA
  original_reference_id: PMID:20209079
  review:
    summary: IDA annotation for defense response to Gram-positive bacterium. These
      immune/inflammatory effects are primarily mediated by Abeta cleavage products
      activating innate immune cells (microglia, astrocytes) rather than representing
      core functions of full-length APP.
    action: KEEP_AS_NON_CORE
    reason: Immune/inflammatory annotation (defense response to Gram-positive bacterium)
      reflects downstream Abeta-mediated effects. Not a core function of APP itself.
      Keep as non-core.
    supported_by:
    - reference_id: PMID:20209079
      supporting_text: The synthetic Abeta peptides demonstrated antibiotic activity
        against Gram-negative and Gram-positive bacteria and the yeast C. albicans
- term:
    id: GO:0031904
    label: endosome lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6783332
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11238726
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:11238726
      supporting_text: Fibulin-1 binds the amino-terminal head of beta-amyloid precursor
        protein and modulates its physiological function.
- term:
    id: GO:0005768
    label: endosome
  evidence_type: IDA
  original_reference_id: PMID:18353773
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:18353773
      supporting_text: 2008 Mar 19. A novel sorting nexin modulates endocytic trafficking
        and alpha-secretase cleavage of the amyloid precursor protein.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:18353773
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:18353773
      supporting_text: 2008 Mar 19. A novel sorting nexin modulates endocytic trafficking
        and alpha-secretase cleavage of the amyloid precursor protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24336208
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:24336208
      supporting_text: Rare coding variants in the phospholipase D3 gene confer risk
        for Alzheimer's disease.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: HDA
  original_reference_id: PMID:16502470
  review:
    summary: HDA annotation from high-throughput direct assay.
    action: ACCEPT
    reason: HDA annotation supported by experimental data.
    supported_by:
    - reference_id: PMID:16502470
      supporting_text: 'Human colostrum: identification of minor proteins in the aqueous
        phase by proteomics.'
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:24499793
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:24499793
      supporting_text: FKBP12 regulates the localization and processing of amyloid
        precursor protein in human cell lines.
- term:
    id: GO:0045121
    label: membrane raft
  evidence_type: IDA
  original_reference_id: PMID:24499793
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:24499793
      supporting_text: FKBP12 regulates the localization and processing of amyloid
        precursor protein in human cell lines.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16407538
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:16407538
      supporting_text: Interaction of the cytosolic domains of sorLA/LR11 with the
        amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving
        enzyme.
- term:
    id: GO:0005641
    label: nuclear envelope lumen
  evidence_type: IDA
  original_reference_id: PMID:21989385
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:21989385
      supporting_text: Quantitative modelling of amyloidogenic processing and its
        influence by SORLA in Alzheimer's disease.
- term:
    id: GO:0043235
    label: receptor complex
  evidence_type: IDA
  original_reference_id: PMID:23382219
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:23382219
      supporting_text: Structural basis for endosomal trafficking of diverse transmembrane
        cargos by PX-FERM proteins.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  review:
    summary: HDA annotation from high-throughput direct assay.
    action: ACCEPT
    reason: HDA annotation supported by experimental data.
    supported_by:
    - reference_id: PMID:19199708
      supporting_text: Proteomic analysis of human parotid gland exosomes by multidimensional
        protein identification technology (MudPIT).
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:20427278
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:20427278
      supporting_text: 2010 Apr 28. The novel membrane protein TMEM59 modulates complex
        glycosylation, cell surface expression, and secretion of the amyloid precursor
        protein.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:20427278
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:20427278
      supporting_text: 2010 Apr 28. The novel membrane protein TMEM59 modulates complex
        glycosylation, cell surface expression, and secretion of the amyloid precursor
        protein.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:20427278
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:20427278
      supporting_text: 2010 Apr 28. The novel membrane protein TMEM59 modulates complex
        glycosylation, cell surface expression, and secretion of the amyloid precursor
        protein.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-481007
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1296421
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-844440
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-844610
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-844612
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0031093
    label: platelet alpha granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-481007
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0031904
    label: endosome lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5229111
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0031904
    label: endosome lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871494
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0031904
    label: endosome lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871506
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0031904
    label: endosome lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9010091
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0032588
    label: trans-Golgi network membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5229111
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0032588
    label: trans-Golgi network membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5229132
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2467665
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6783332
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-879411
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-976734
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-977136
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-997411
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-379048
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-380073
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-391913
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-749448
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-749452
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-749454
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-749456
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8870710
  review:
    summary: TAS annotation from Reactome pathway database.
    action: ACCEPT
    reason: Reactome annotation consistent with known APP biology and pathway involvement.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18468999
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:18468999
      supporting_text: 2008 May 9. Regulation of FE65 nuclear translocation and function
        by amyloid beta-protein precursor in osmotically stressed cells.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:12805363
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:12805363
      supporting_text: 2003 Jun 12. Autosomal recessive hypercholesterolemia protein
        interacts with and regulates the cell surface level of Alzheimer's amyloid
        beta precursor protein.
- term:
    id: GO:0051425
    label: PTB domain binding
  evidence_type: IPI
  original_reference_id: PMID:12805363
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:12805363
      supporting_text: 2003 Jun 12. Autosomal recessive hypercholesterolemia protein
        interacts with and regulates the cell surface level of Alzheimer's amyloid
        beta precursor protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18509662
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:18509662
      supporting_text: 2008 May 29. Close association of water channel AQP1 with amyloid-beta
        deposition in Alzheimer disease brains.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:18509662
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:18509662
      supporting_text: 2008 May 29. Close association of water channel AQP1 with amyloid-beta
        deposition in Alzheimer disease brains.
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IPI
  original_reference_id: PMID:19849849
  review:
    summary: IPI annotation showing specific protein interaction.
    action: ACCEPT
    reason: IPI annotation with specific molecular function is more informative than
      generic protein binding.
    supported_by:
    - reference_id: PMID:19849849
      supporting_text: CD74 interacts with APP and suppresses the production of Abeta.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19849849
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:19849849
      supporting_text: CD74 interacts with APP and suppresses the production of Abeta.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19901339
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:19901339
      supporting_text: RAGE-mediated signaling contributes to intraneuronal transport
        of amyloid-beta and neuronal dysfunction.
- term:
    id: GO:0043197
    label: dendritic spine
  evidence_type: IDA
  original_reference_id: PMID:11988176
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:11988176
      supporting_text: The acid-activated ion channel ASIC contributes to synaptic
        plasticity, learning, and memory.
- term:
    id: GO:0043198
    label: dendritic shaft
  evidence_type: IDA
  original_reference_id: PMID:11988176
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:11988176
      supporting_text: The acid-activated ion channel ASIC contributes to synaptic
        plasticity, learning, and memory.
- term:
    id: GO:0045202
    label: synapse
  evidence_type: IDA
  original_reference_id: PMID:11988176
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:11988176
      supporting_text: The acid-activated ion channel ASIC contributes to synaptic
        plasticity, learning, and memory.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for DNA binding. The AICD fragment has been reported to
      associate with transcription factor complexes (Fe65/Tip60) and regulate gene
      expression, but whether AICD itself directly binds DNA remains controversial.
      Most evidence suggests AICD acts as a transcriptional co-activator through protein-protein
      interactions rather than direct DNA binding.
    action: UNDECIDED
    reason: The claim that APP/AICD directly binds DNA is not well-supported. AICD
      associates with DNA-binding complexes but may not bind DNA directly. This annotation
      needs further experimental validation.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0006417
    label: regulation of translation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0006878
    label: intracellular copper ion homeostasis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0006897
    label: endocytosis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0007409
    label: axonogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0007617
    label: mating behavior
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for mating behavior based on mouse APP knockout/transgenic
      studies. These behavioral phenotypes reflect pleiotropic downstream effects
      of APP loss or Abeta overexpression in mice rather than a core molecular function
      of APP.
    action: KEEP_AS_NON_CORE
    reason: Behavioral phenotype (mating behavior) observed in mouse models. Not a
      core function of APP but a downstream consequence. Keep as non-core.
- term:
    id: GO:0007626
    label: locomotory behavior
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for locomotory behavior based on mouse APP knockout/transgenic
      studies. These behavioral phenotypes reflect pleiotropic downstream effects
      of APP loss or Abeta overexpression in mice rather than a core molecular function
      of APP.
    action: KEEP_AS_NON_CORE
    reason: Behavioral phenotype (locomotory behavior) observed in mouse models. Not
      a core function of APP but a downstream consequence. Keep as non-core.
- term:
    id: GO:0008088
    label: axo-dendritic transport
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0008344
    label: adult locomotory behavior
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for adult locomotory behavior based on mouse APP knockout/transgenic
      studies. These behavioral phenotypes reflect pleiotropic downstream effects
      of APP loss or Abeta overexpression in mice rather than a core molecular function
      of APP.
    action: KEEP_AS_NON_CORE
    reason: Behavioral phenotype (adult locomotory behavior) observed in mouse models.
      Not a core function of APP but a downstream consequence. Keep as non-core.
- term:
    id: GO:0008542
    label: visual learning
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for visual learning based on mouse APP knockout/transgenic
      studies. These behavioral phenotypes reflect pleiotropic downstream effects
      of APP loss or Abeta overexpression in mice rather than a core molecular function
      of APP.
    action: KEEP_AS_NON_CORE
    reason: Behavioral phenotype (visual learning) observed in mouse models. Not a
      core function of APP but a downstream consequence. Keep as non-core.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0016199
    label: axon midline choice point recognition
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0016322
    label: neuron remodeling
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0016358
    label: dendrite development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0030198
    label: extracellular matrix organization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0030424
    label: axon
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0031175
    label: neuron projection development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0035235
    label: ionotropic glutamate receptor signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0040014
    label: regulation of multicellular organism growth
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0045931
    label: positive regulation of mitotic cell cycle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for positive regulation of mitotic cell cycle. Some evidence
      suggests AICD can regulate cell cycle genes, but this is not a core function
      of APP in neurons (which are post-mitotic).
    action: KEEP_AS_NON_CORE
    reason: Cell cycle regulation is not a core function of APP, particularly in neurons
      which are post-mitotic. Keep as non-core.
- term:
    id: GO:0048669
    label: collateral sprouting in absence of injury
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0050803
    label: regulation of synapse structure or activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity to characterized ortholog.
    action: ACCEPT
    reason: ISS annotation consistent with known APP functions.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18026102
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:18026102
      supporting_text: Cystatin C modulates cerebral beta-amyloidosis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14557245
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:14557245
      supporting_text: APP-BP1 mediates APP-induced apoptosis and DNA synthesis and
        is increased in Alzheimer's disease brain.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8626687
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:8626687
      supporting_text: APP-BP1, a novel protein that binds to the carboxyl-terminal
        region of the amyloid precursor protein.
- term:
    id: GO:0004867
    label: serine-type endopeptidase inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:10652580
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:10652580
      supporting_text: Production of amyloid beta protein precursor as a proteinase
        inhibitor by human astrocytic tumors.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:7593229
  review:
    summary: IDA annotation based on direct experimental assay.
    action: ACCEPT
    reason: IDA annotation supported by direct experimental evidence.
    supported_by:
    - reference_id: PMID:7593229
      supporting_text: 'Serine proteinase inhibitors in human skeletal muscle: expression
        of beta-amyloid protein precursor and alpha 1-antichymotrypsin in vivo and
        during myogenesis in vitro.'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:10806211
  review:
    summary: TAS annotation based on author statement in referenced publication.
    action: ACCEPT
    reason: TAS annotation supported by literature.
    supported_by:
    - reference_id: PMID:10806211
      supporting_text: Phosphorylation of the beta-amyloid precursor protein at the
        cell surface by ectocasein kinases 1 and 2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10081969
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:10081969
      supporting_text: Molecular cloning of human Fe65L2 and its interaction with
        the Alzheimer's beta-amyloid precursor protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10049767
  review:
    summary: IPI protein binding annotation. Generic protein binding does not provide
      specific functional information.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding uninformative - should use more specific MF terms.
    supported_by:
    - reference_id: PMID:10049767
      supporting_text: X11L2, a new member of the X11 protein family, interacts with
        Alzheimer's beta-amyloid precursor protein.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000114
  title: Manual transfer of experimentally-verified manual GO annotation data to homologous
    complexes by curator judgment of sequence, composition and function similarity
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10049767
  title: X11L2, a new member of the X11 protein family, interacts with Alzheimer's
    beta-amyloid precursor protein.
  findings: []
- id: PMID:10081969
  title: Molecular cloning of human Fe65L2 and its interaction with the Alzheimer's
    beta-amyloid precursor protein.
  findings: []
- id: PMID:10652580
  title: Production of amyloid beta protein precursor as a proteinase inhibitor by
    human astrocytic tumors.
  findings: []
- id: PMID:10673326
  title: Agrin binds to beta-amyloid (Abeta), accelerates abeta fibril formation,
    and is localized to Abeta deposits in Alzheimer's disease brain.
  findings: []
- id: PMID:10677483
  title: Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid
    precursor protein.
  findings: []
- id: PMID:10681545
  title: beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with
    high affinity. Implications for Alzheimer's disease pathology.
  findings: []
- id: PMID:10806211
  title: Phosphorylation of the beta-amyloid precursor protein at the cell surface
    by ectocasein kinases 1 and 2.
  findings: []
- id: PMID:11140684
  title: A learning deficit related to age and beta-amyloid plaques in a mouse model
    of Alzheimer's disease.
  findings: []
- id: PMID:11238726
  title: Fibulin-1 binds the amino-terminal head of beta-amyloid precursor protein
    and modulates its physiological function.
  findings: []
- id: PMID:11278849
  title: beta -Amyloid peptide-induced apoptosis regulated by a novel protein containing
    a g protein activation module.
  findings: []
- id: PMID:11297421
  title: Apolipoprotein A-I directly interacts with amyloid precursor protein and
    inhibits A beta aggregation and toxicity.
  findings: []
- id: PMID:11404397
  title: 'Beta-amyloid activates the mitogen-activated protein kinase cascade via
    hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms
    related to Alzheimer''s disease.'
  findings: []
- id: PMID:11724784
  title: Jun NH2-terminal kinase (JNK) interacting protein 1 (JIP1) binds the cytoplasmic
    domain of the Alzheimer's beta-amyloid precursor protein (APP).
  findings: []
- id: PMID:11756426
  title: Amyloid beta binds trimers as well as monomers of the 75-kDa neurotrophin
    receptor and activates receptor signaling.
  findings: []
- id: PMID:11877420
  title: Tyrosine phosphorylation of the beta-amyloid precursor protein cytoplasmic
    tail promotes interaction with Shc.
  findings: []
- id: PMID:11880515
  title: The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's
    disease.
  findings: []
- id: PMID:11988176
  title: The acid-activated ion channel ASIC contributes to synaptic plasticity, learning,
    and memory.
  findings: []
- id: PMID:12054541
  title: A secreted form of human ADAM9 has an alpha-secretase activity for APP.
  findings: []
- id: PMID:12485888
  title: Signal transduction through tyrosine-phosphorylated carboxy-terminal fragments
    of APP via an enhanced interaction with Shc/Grb2 adaptor proteins in reactive
    astrocytes of Alzheimer's disease brain.
  findings: []
- id: PMID:12805363
  title: Autosomal recessive hypercholesterolemia protein interacts with and regulates
    the cell surface level of Alzheimer's amyloid beta precursor protein.
  findings: []
- id: PMID:12808450
  title: RAGE mediates amyloid-beta peptide transport across the blood-brain barrier
    and accumulation in brain.
  findings: []
- id: PMID:12901838
  title: Presenilin-1 interacts directly with the beta-site amyloid protein precursor
    cleaving enzyme (BACE1).
  findings: []
- id: PMID:14527950
  title: Generation of the beta-amyloid peptide and the amyloid precursor protein
    C-terminal fragment gamma are potentiated by FE65L1.
  findings: []
- id: PMID:14557245
  title: APP-BP1 mediates APP-induced apoptosis and DNA synthesis and is increased
    in Alzheimer's disease brain.
  findings: []
- id: PMID:15447668
  title: MAPK recruitment by beta-amyloid in organotypic hippocampal slice cultures
    depends on physical state and exposure time.
  findings: []
- id: PMID:15457210
  title: RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic
    mice.
  findings: []
- id: PMID:15615705
  title: CLAC binds to amyloid beta peptides through the positively charged amino
    acid cluster within the collagenous domain 1 and inhibits formation of amyloid
    fibrils.
  findings: []
- id: PMID:15896298
  title: In cerebrospinal fluid ER chaperones ERp57 and calreticulin bind beta-amyloid.
  findings: []
- id: PMID:16027166
  title: BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid
    beta (Abeta) production.
  findings: []
- id: PMID:16049941
  title: A pilot proteomic study of amyloid precursor interactors in Alzheimer's disease.
  findings: []
- id: PMID:16174740
  title: Neuronal sorting protein-related receptor sorLA/LR11 regulates processing
    of the amyloid precursor protein.
  findings: []
- id: PMID:16286452
  title: Gerstmann-Sträussler-Scheinker disease amyloid protein polymerizes according
    to the "dock-and-lock" model.
  findings: []
- id: PMID:16374483
  title: Neurofibromatosis type 1 protein and amyloid precursor protein interact in
    normal human melanocytes and colocalize with melanosomes.
  findings: []
- id: PMID:16407538
  title: Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor
    protein (APP) and beta-secretase beta-site APP-cleaving enzyme.
  findings: []
- id: PMID:16446437
  title: Abeta and tau form soluble complexes that may promote self aggregation of
    both into the insoluble forms observed in Alzheimer's disease.
  findings: []
- id: PMID:16480949
  title: The intracellular domain of amyloid precursor protein interacts with flotillin-1,
    a lipid raft protein.
  findings: []
- id: PMID:16502470
  title: 'Human colostrum: identification of minor proteins in the aqueous phase by
    proteomics.'
  findings: []
- id: PMID:16554819
  title: The prolyl isomerase Pin1 regulates amyloid precursor protein processing
    and amyloid-beta production.
  findings: []
- id: PMID:16636059
  title: Neprilysin-sensitive synapse-associated amyloid-beta peptide oligomers impair
    neuronal plasticity and cognitive function.
  findings: []
- id: PMID:17051221
  title: Structures of human insulin-degrading enzyme reveal a new substrate recognition
    mechanism.
  findings: []
- id: PMID:17112471
  title: ADAM19 is tightly associated with constitutive Alzheimer's disease APP alpha-secretase
    in A172 cells.
  findings: []
- id: PMID:17112520
  title: 'Aluminum inhibits proteolytic degradation of amyloid beta peptide by cathepsin
    D: a potential link between aluminum accumulation and neuritic plaque deposition.'
  findings: []
- id: PMID:17116874
  title: Blocking the apolipoprotein E/amyloid-beta interaction as a potential therapeutic
    approach for Alzheimer's disease.
  findings: []
- id: PMID:17251419
  title: Abeta oligomer-induced aberrations in synapse composition, shape, and density
    provide a molecular basis for loss of connectivity in Alzheimer's disease.
  findings: []
- id: PMID:17255335
  title: Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque
    deposition and beta-secretase expression in Swedish mutant APP transgenic mice.
  findings: []
- id: PMID:17308309
  title: Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate
    receptor-dependent mechanism that is blocked by the Alzheimer drug memantine.
  findings: []
- id: PMID:17360908
  title: Natural oligomers of the Alzheimer amyloid-beta protein induce reversible
    synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling
    pathway.
  findings: []
- id: PMID:17709753
  title: Amyolid precursor protein mediates presynaptic localization and activity
    of the high-affinity choline transporter.
  findings: []
- id: PMID:18026102
  title: Cystatin C modulates cerebral beta-amyloidosis.
  findings: []
- id: PMID:18059284
  title: Evidence of fibril-like β-sheet structures in a neurotoxic amyloid intermediate
    of Alzheimer's β-amyloid.
  findings: []
- id: PMID:18234671
  title: Amyloid-beta binds to the extracellular cysteine-rich domain of Frizzled
    and inhibits Wnt/beta-catenin signaling.
  findings: []
- id: PMID:18353773
  title: A novel sorting nexin modulates endocytic trafficking and alpha-secretase
    cleavage of the amyloid precursor protein.
  findings: []
- id: PMID:18468999
  title: Regulation of FE65 nuclear translocation and function by amyloid beta-protein
    precursor in osmotically stressed cells.
  findings: []
- id: PMID:18483195
  title: Paired beta-sheet structure of an Abeta(1-40) amyloid fibril revealed by
    electron microscopy.
  findings: []
- id: PMID:18499799
  title: Two-dimensional infrared spectra of isotopically diluted amyloid fibrils
    from Abeta40.
  findings: []
- id: PMID:18509662
  title: Close association of water channel AQP1 with amyloid-beta deposition in Alzheimer
    disease brains.
  findings: []
- id: PMID:18568035
  title: Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair
    synaptic plasticity and memory.
  findings: []
- id: PMID:18602473
  title: 'Aggregation and catabolism of disease-associated intra-Abeta mutations:
    reduced proteolysis of AbetaA21G by neprilysin.'
  findings: []
- id: PMID:18805418
  title: 'In vitro perturbation of aggregation processes in beta-amyloid peptides:
    a spectroscopic study.'
  findings: []
- id: PMID:18806802
  title: Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation
    and ameliorates learning and memory in Alzheimer's disease.
  findings: []
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein
    identification technology (MudPIT).
  findings: []
- id: PMID:19242475
  title: Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta
    oligomers.
  findings: []
- id: PMID:19304802
  title: Synaptic transmission block by presynaptic injection of oligomeric amyloid
    beta.
  findings: []
- id: PMID:19458258
  title: Alpha-helix targeting reduces amyloid-beta peptide toxicity.
  findings: []
- id: PMID:19549187
  title: Quenched hydrogen/deuterium exchange NMR characterization of amyloid-beta
    peptide aggregates formed in the presence of Cu2+ or Zn2+.
  findings: []
- id: PMID:19587288
  title: Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive
    deficits and synaptic pathology in a mouse model of Alzheimer's disease.
  findings: []
- id: PMID:19660551
  title: Biochemical and immunohistochemical analysis of an Alzheimer's disease mouse
    model reveals the presence of multiple cerebral Abeta assembly forms throughout
    life.
  findings: []
- id: PMID:19706468
  title: Structure-neurotoxicity relationships of amyloid beta-protein oligomers.
  findings: []
- id: PMID:19706519
  title: Measurement of amyloid fibril mass-per-length by tilted-beam transmission
    electron microscopy.
  findings: []
- id: PMID:19726636
  title: Presynaptic and postsynaptic interaction of the amyloid precursor protein
    promotes peripheral and central synaptogenesis.
  findings: []
- id: PMID:19754881
  title: The thioflavin T fluorescence assay for amyloid fibril detection can be biased
    by the presence of exogenous compounds.
  findings: []
- id: PMID:19841277
  title: Site-specific modification of Alzheimer's peptides by cholesterol oxidation
    products enhances aggregation energetics and neurotoxicity.
  findings: []
- id: PMID:19849849
  title: CD74 interacts with APP and suppresses the production of Abeta.
  findings: []
- id: PMID:19901339
  title: RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta
    and neuronal dysfunction.
  findings: []
- id: PMID:20032460
  title: Inhibition of calcineurin-mediated endocytosis and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
    acid (AMPA) receptors prevents amyloid beta oligomer-induced synaptic disruption.
  findings: []
- id: PMID:20133839
  title: Mechanism of amyloid plaque formation suggests an intracellular basis of
    Abeta pathogenicity.
  findings: []
- id: PMID:20164328
  title: Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation,
    exacerbating early-stage cognitive decline and septohippocampal pathology in a
    mouse model of Alzheimer's disease.
  findings: []
- id: PMID:20195357
  title: A comprehensive resource of interacting protein regions for refining human
    transcription factor networks.
  findings: []
- id: PMID:20209079
  title: The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial
    peptide.
  findings: []
- id: PMID:20427278
  title: The novel membrane protein TMEM59 modulates complex glycosylation, cell surface
    expression, and secretion of the amyloid precursor protein.
  findings: []
- id: PMID:20445063
  title: Memory impairment in transgenic Alzheimer mice requires cellular prion protein.
  findings: []
- id: PMID:20573181
  title: Progressive accumulation of amyloid-beta oligomers in Alzheimer's disease
    and in amyloid precursor protein transgenic mice is accompanied by selective alterations
    in synaptic scaffold proteins.
  findings: []
- id: PMID:20811458
  title: Gamma-secretase activating protein is a therapeutic target for Alzheimer's
    disease.
  findings: []
- id: PMID:20817278
  title: Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited
    by zinc in Alzheimer's disease.
  findings: []
- id: PMID:20818335
  title: Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes
    in the Aβ42 to Aβ40 ratio.
  findings: []
- id: PMID:20828565
  title: An aminopeptidase from Streptomyces sp. KK565 degrades beta amyloid monomers,
    oligomers and fibrils.
  findings: []
- id: PMID:20974225
  title: Activation of nicotinic α(7) acetylcholine receptor enhances long term potentation
    in wild type mice but not in APP(swe)/PS1ΔE9 mice.
  findings: []
- id: PMID:21113149
  title: Reversing EphB2 depletion rescues cognitive functions in Alzheimer model.
  findings: []
- id: PMID:21126803
  title: Perlecan domain V inhibits α2 integrin-mediated amyloid-β neurotoxicity.
  findings: []
- id: PMID:21163940
  title: Interactome mapping suggests new mechanistic details underlying Alzheimer's
    disease.
  findings: []
- id: PMID:2119582
  title: Transforming growth factor-beta bound to soluble derivatives of the beta
    amyloid precursor protein of Alzheimer's disease.
  findings: []
- id: PMID:21205198
  title: Lysophosphatidylcholine modulates fibril formation of amyloid beta peptide.
  findings: []
- id: PMID:21289173
  title: Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related
    protein 1 constitute major pathways for neuronal amyloid-beta uptake.
  findings: []
- id: PMID:21293490
  title: Mediator is a transducer of amyloid-precursor-protein-dependent nuclear signalling.
  findings: []
- id: PMID:21320494
  title: Lipid matrix plays a role in Abeta fibril kinetics and morphology.
  findings: []
- id: PMID:21527912
  title: Extracellular phosphorylation of the amyloid β-peptide promotes formation
    of toxic aggregates during the pathogenesis of Alzheimer's disease.
  findings: []
- id: PMID:21857966
  title: WNT5A signaling contributes to Aβ-induced neuroinflammation and neurotoxicity.
  findings: []
- id: PMID:21989385
  title: Quantitative modelling of amyloidogenic processing and its influence by SORLA
    in Alzheimer's disease.
  findings: []
- id: PMID:22036569
  title: Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent
    β-amyloid generation.
  findings: []
- id: PMID:22138302
  title: Preferential interactions between ApoE-containing lipoproteins and Aβ revealed
    by a detection method that combines size exclusion chromatography with non-reducing
    gel-shift.
  findings: []
- id: PMID:22179788
  title: The extracellular chaperone clusterin sequesters oligomeric forms of the
    amyloid-β(1-40) peptide.
  findings: []
- id: PMID:22198949
  title: TLR2 is a primary receptor for Alzheimer's amyloid β peptide to trigger neuroinflammatory
    activation.
  findings: []
- id: PMID:22200570
  title: Effect of N-homocysteinylation on physicochemical and cytotoxic properties
    of amyloid β-peptide.
  findings: []
- id: PMID:22406537
  title: A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder
    in a mouse model of Alzheimer disease.
  findings: []
- id: PMID:22500019
  title: Amyloid β (Aβ) peptide directly activates amylin-3 receptor subtype by triggering
    multiple intracellular signaling pathways.
  findings: []
- id: PMID:22528093
  title: Search for amyloid-binding proteins by affinity chromatography.
  findings: []
- id: PMID:22584060
  title: Dimeric structure of transmembrane domain of amyloid precursor protein in
    micellar environment.
  findings: []
- id: PMID:22730553
  title: Open-closed motion of Mint2 regulates APP metabolism.
  findings: []
- id: PMID:22801501
  title: A mutation in APP protects against Alzheimer's disease and age-related cognitive
    decline.
  findings: []
- id: PMID:22820466
  title: Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates
    Fyn to impair neurons.
  findings: []
- id: PMID:22944668
  title: 'Antimicrobial activity of human islet amyloid polypeptides: an insight into
    amyloid peptides'' connection with antimicrobial peptides.'
  findings: []
- id: PMID:23103738
  title: A comparative analysis of the aggregation behavior of amyloid-β peptide variants.
  findings: []
- id: PMID:23106396
  title: Amyloid-β oligomers are sequestered by both intracellular and extracellular
    chaperones.
  findings: []
- id: PMID:23152628
  title: LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer's
    amyloid-β.
  findings: []
- id: PMID:23164821
  title: Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of
    the wnt-PCP-JNK pathway.
  findings: []
- id: PMID:23353684
  title: Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via
    two distinct mechanisms.
  findings: []
- id: PMID:23382219
  title: Structural basis for endosomal trafficking of diverse transmembrane cargos
    by PX-FERM proteins.
  findings: []
- id: PMID:23416305
  title: Interaction between soluble Aβ-(1-40) monomer and Aβ-(1-42) fibrils probed
    by paramagnetic relaxation enhancement.
  findings: []
- id: PMID:23525105
  title: Transcriptional regulation of insulin-degrading enzyme modulates mitochondrial
    amyloid β (Aβ) peptide catabolism and functionality.
  findings: []
- id: PMID:23551356
  title: N-terminal domain of Pyrococcus furiosus l-asparaginase functions as a non-specific,
    stable, molecular chaperone.
  findings: []
- id: PMID:23585889
  title: Generation of amyloid-β is reduced by the interaction of calreticulin with
    amyloid precursor protein, presenilin and nicastrin.
  findings: []
- id: PMID:23603391
  title: NMR characterization of the interaction of GroEL with amyloid β as a model
    ligand.
  findings: []
- id: PMID:23640054
  title: Brain interstitial oligomeric amyloid β increases with age and is resistant
    to clearance from brain in a mouse model of Alzheimer's disease.
  findings: []
- id: PMID:23907009
  title: Isobavachalcone and bavachinin from Psoraleae Fructus modulate Aβ42 aggregation
    process through different mechanisms in vitro.
  findings: []
- id: PMID:23921129
  title: FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer's
    disease.
  findings: []
- id: PMID:23973487
  title: Two β-strands of RAGE participate in the recognition and transport of amyloid-β
    peptide across the blood brain barrier.
  findings: []
- id: PMID:24012003
  title: Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer
    bound to cellular prion protein.
  findings: []
- id: PMID:24028865
  title: Impact of the cellular prion protein on amyloid-β and 3PO-tau processing.
  findings: []
- id: PMID:24052308
  title: Human LilrB2 is a β-amyloid receptor and its murine homolog PirB regulates
    synaptic plasticity in an Alzheimer's model.
  findings: []
- id: PMID:24065130
  title: Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule
    severing by TTLL6 and spastin.
  findings: []
- id: PMID:24284412
  title: Amyloid beta a4 precursor protein-binding family B member 1 (FE65) interactomics
    revealed synaptic vesicle glycoprotein 2A (SV2A) and sarcoplasmic/endoplasmic
    reticulum calcium ATPase 2 (SERCA2) as new binding proteins in the human brain.
  findings: []
- id: PMID:24305806
  title: Pharmacologic inhibition of ROCK2 suppresses amyloid-β production in an Alzheimer's
    disease mouse model.
  findings: []
- id: PMID:24336208
  title: Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's
    disease.
  findings: []
- id: PMID:24499793
  title: FKBP12 regulates the localization and processing of amyloid precursor protein
    in human cell lines.
  findings: []
- id: PMID:24720730
  title: The coexistence of an equal amount of Alzheimer's amyloid-β 40 and 42 forms
    structurally stable and toxic oligomers through a distinct pathway.
  findings: []
- id: PMID:24867889
  title: sAPP modulates iron efflux from brain microvascular endothelial cells by
    stabilizing the ferrous iron exporter ferroportin.
  findings: []
- id: PMID:24931469
  title: Molecular basis of substrate recognition and degradation by human presequence
    protease.
  findings: []
- id: PMID:25241761
  title: Using an in situ proximity ligation assay to systematically profile endogenous
    protein-protein interactions in a pathway network.
  findings: []
- id: PMID:25543257
  title: Modeling an in-register, parallel "iowa" aβ fibril structure using solid-state
    NMR data from labeled samples with rosetta.
  findings: []
- id: PMID:25620700
  title: A genome-wide gene-expression analysis and database in transgenic mice during
    development of amyloid or tau pathology.
  findings: []
- id: PMID:25643321
  title: Structural basis for amyloidogenic peptide recognition by sorLA.
  findings: []
- id: PMID:25897080
  title: Sequential Amyloid-β Degradation by the Matrix Metalloproteases MMP-2 and
    MMP-9.
  findings: []
- id: PMID:25959826
  title: Quantitative interaction proteomics of neurodegenerative disease proteins.
  findings: []
- id: PMID:26005850
  title: Central role for PICALM in amyloid-β blood-brain barrier transcytosis and
    clearance.
  findings: []
- id: PMID:26006083
  title: The multidrug resistance pump ABCB1 is a substrate for the ubiquitin ligase
    NEDD4-1.
  findings: []
- id: PMID:26138908
  title: High-resolution NMR characterization of low abundance oligomers of amyloid-β
    without purification.
  findings: []
- id: PMID:26200696
  title: Dual pathways mediate β-amyloid stimulated glutathione release from astrocytes.
  findings: []
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries
    and abundances.
  findings: []
- id: PMID:26618561
  title: Direct High Affinity Interaction between Aβ42 and GSK3α Stimulates Hyperphosphorylation
    of Tau. A New Molecular Link in Alzheimer's Disease?
  findings: []
- id: PMID:27853422
  title: ROCK1 Is Associated with Alzheimer's Disease-Specific Plaques, as well as
    Enhances Autophagosome Formation But not Autophagic Aβ Clearance.
  findings: []
- id: PMID:28008308
  title: The Protective Role of microRNA-200c in Alzheimer's Disease Pathologies Is
    Induced by Beta Amyloid-Triggered Endoplasmic Reticulum Stress.
  findings: []
- id: PMID:28164773
  title: Apolipoprotein E-mediated Modulation of ADAM10 in Alzheimer's Disease.
  findings: []
- id: PMID:28720718
  title: Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD
    activity and neurotoxicity in Parkinson's disease.
  findings: []
- id: PMID:28855300
  title: An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and
    affects shedding and phagocytic function.
  findings: []
- id: PMID:28882996
  title: Fibril structure of amyloid-β(1-42) by cryo-electron microscopy.
  findings: []
- id: PMID:29061364
  title: Inflammatory microglia are glycolytic and iron retentive and typify the microglia
    in APP/PS1 mice.
  findings: []
- id: PMID:29274751
  title: Reduced expression of Na(+)/Ca(2+) exchangers is associated with cognitive
    deficits seen in Alzheimer's disease model mice.
  findings: []
- id: PMID:29423001
  title: Hypoxia increases amyloid-β level in exosomes by enhancing the interaction
    between CD147 and Hook1.
  findings: []
- id: PMID:29518356
  title: TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function.
  findings: []
- id: PMID:29578633
  title: Probing the Mint2 Protein-Protein Interaction Network Relevant to the Pathophysiology
    of Alzheimer's Disease.
  findings: []
- id: PMID:29961672
  title: miR-15b reduces amyloid-β accumulation in SH-SY5Y cell line through targetting
    NF-κB signaling and BACE1.
  findings: []
- id: PMID:30086173
  title: TMEM30A is a candidate interacting partner for the β-carboxyl-terminal fragment
    of amyloid-β precursor protein in endosomes.
  findings: []
- id: PMID:30158114
  title: TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer's disease.
  findings: []
- id: PMID:30538620
  title: Visualization of Alzheimer's Disease Related α-/β-/γ-Secretase Ternary Complex
    by Bimolecular Fluorescence Complementation Based Fluorescence Resonance Energy
    Transfer.
  findings: []
- id: PMID:31413325
  title: HENA, heterogeneous network-based data set for Alzheimer's disease.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33239400
  title: Implications of Oligomeric Amyloid-Beta (oAβ(42)) Signaling through α7β2-Nicotinic
    Acetylcholine Receptors (nAChRs) on Basal Forebrain Cholinergic Neuronal Intrinsic
    Excitability and Cognitive Decline.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34446781
  title: First identification of ITM2B interactome in the human retina.
  findings: []
- id: PMID:35063084
  title: Tau interactome maps synaptic and mitochondrial processes associated with
    neurodegeneration.
  findings: []
- id: PMID:35914814
  title: 'Chr21 protein-protein interactions: enrichment in proteins involved in intellectual
    disability, autism, and late-onset Alzheimer''s disease.'
  findings: []
- id: PMID:35922511
  title: A physical wiring diagram for the human immune system.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:7593229
  title: 'Serine proteinase inhibitors in human skeletal muscle: expression of beta-amyloid
    protein precursor and alpha 1-antichymotrypsin in vivo and during myogenesis in
    vitro.'
  findings: []
- id: PMID:8626687
  title: APP-BP1, a novel protein that binds to the carboxyl-terminal region of the
    amyloid precursor protein.
  findings: []
- id: PMID:8855266
  title: Association of a novel human FE65-like protein with the cytoplasmic domain
    of the beta-amyloid precursor protein.
  findings: []
- id: PMID:8887653
  title: The phosphotyrosine interaction domains of X11 and FE65 bind to distinct
    sites on the YENPTY motif of amyloid precursor protein.
  findings: []
- id: PMID:9211985
  title: Association of human, rat, and rabbit apolipoprotein E with beta-amyloid.
  findings: []
- id: PMID:9223340
  title: 'Interaction between amyloid precursor protein and presenilins in mammalian
    cells: implications for the pathogenesis of Alzheimer disease.'
  findings: []
- id: PMID:9228033
  title: Interaction of apolipoprotein J-amyloid beta-peptide complex with low density
    lipoprotein receptor-related protein-2/megalin. A mechanism to prevent pathological
    accumulation of amyloid beta-peptide.
  findings: []
- id: PMID:9338779
  title: An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity
    in Alzheimer's disease.
  findings: []
- id: PMID:9461550
  title: 'Fe65L2: a new member of the Fe65 protein family interacting with the intracellular
    domain of the Alzheimer''s beta-amyloid precursor protein.'
  findings: []
- id: PMID:9737846
  title: Solution structure of methionine-oxidized amyloid beta-peptide (1-40). Does
    oxidation affect conformational switching?
  findings: []
- id: PMID:9774383
  title: Evidence that tumor necrosis factor alpha converting enzyme is involved in
    regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor.
  findings: []
- id: Reactome:R-HSA-1296421
  title: NLRP3 oligomerizes via NACHT domains
  findings: []
- id: Reactome:R-HSA-2467665
  title: AGRN binds Beta amyloid fibril via GAG chains
  findings: []
- id: Reactome:R-HSA-379048
  title: Liganded Gq/11-activating GPCRs act as GEFs for Gq/11
  findings: []
- id: Reactome:R-HSA-380073
  title: Liganded Gi-activating GPCR acts as a GEF for Gi
  findings: []
- id: Reactome:R-HSA-391913
  title: FPR2 binds FPR2 ligands
  findings: []
- id: Reactome:R-HSA-481007
  title: Exocytosis of platelet alpha granule contents
  findings: []
- id: Reactome:R-HSA-5229111
  title: AP4 transports APP from trans-Golgi network to endosome lumen
  findings: []
- id: Reactome:R-HSA-5229132
  title: AP4 binds APP
  findings: []
- id: Reactome:R-HSA-5692495
  title: BACE1 cleaves APP(18-770) to APP(18-671) and APP(672-770)
  findings: []
- id: Reactome:R-HSA-6783332
  title: APP(672-713),APP(672-711) translocate from endosome lumen to extracellular
    region
  findings: []
- id: Reactome:R-HSA-749448
  title: Liganded Gq-activating GPCRs bind inactive heterotrimeric Gq
  findings: []
- id: Reactome:R-HSA-749452
  title: The Ligand:GPCR:Gq complex dissociates
  findings: []
- id: Reactome:R-HSA-749454
  title: The Ligand:GPCR:Gi complex dissociates
  findings: []
- id: Reactome:R-HSA-749456
  title: Liganded Gi-activating GPCRs bind inactive heterotrimeric G-protein Gi
  findings: []
- id: Reactome:R-HSA-844440
  title: NLRP3 activation by elicitor proteins
  findings: []
- id: Reactome:R-HSA-844610
  title: NLRP3 recruits PYCARD (ASC) via a PYD-PYD interaction
  findings: []
- id: Reactome:R-HSA-844612
  title: PYCARD recruits procaspase-1 via CARD
  findings: []
- id: Reactome:R-HSA-879411
  title: Advanced glycosylation end product-specific receptor (AGER/RAGE) is a multiligand
    receptor
  findings: []
- id: Reactome:R-HSA-8870710
  title: APP gene expression
  findings: []
- id: Reactome:R-HSA-8871494
  title: SORL1 binds APP(18-770)
  findings: []
- id: Reactome:R-HSA-8871506
  title: SORL1 transports APP(18-770) from endosome lumen to Golgi lumen
  findings: []
- id: Reactome:R-HSA-8952289
  title: FAM20C phosphorylates FAM20C substrates
  findings: []
- id: Reactome:R-HSA-9010034
  title: ADAM10:Zn2+:TSPANs cleaves APP(18-770)
  findings: []
- id: Reactome:R-HSA-9010091
  title: APP translocates from plasma membrane to endosome lumen
  findings: []
- id: Reactome:R-HSA-9010096
  title: Gamma-secretase cleaves APP(672-770) to APP(672-711) and APP(672-713)
  findings: []
- id: Reactome:R-HSA-9617595
  title: SGTA binds mislocalized membrane protein
  findings: []
- id: Reactome:R-HSA-976734
  title: Amyloid fibrils have additional components
  findings: []
- id: Reactome:R-HSA-977136
  title: Amyloid precursor proteins form ordered fibrils
  findings: []
- id: Reactome:R-HSA-9839072
  title: HTRA2 degrades APP (Amyloid-beta precursor protein)
  findings: []
- id: Reactome:R-NUL-997411
  title: AGER binds rat ERK1/2
  findings: []
core_functions:
  - description: Full-length APP functions as a cell surface adhesion molecule. APP
      molecules on neighboring cells engage in trans-dimerization to promote
      synaptogenesis and cell-cell contact. This is a physiological function of
      full-length APP at the plasma membrane.
    molecular_function:
      id: GO:0098631
      label: cell adhesion mediator activity
    directly_involved_in:
      - id: GO:0007155
        label: cell adhesion
    locations:
      - id: GO:0005886
        label: plasma membrane
      - id: GO:0009986
        label: cell surface
    supported_by:
      - reference_id: file:human/APP/APP-deep-research-falcon.md
  - description: APP regulates axon development through multiple mechanisms. The
      sAPPalpha ectodomain promotes neurite outgrowth acting as a signaling
      ligand, while full-length APP interacts with Fe65/Mena to guide axon
      growth. APP knockout mice show defects in axonogenesis.
    molecular_function:
      id: GO:0030546
      label: signaling receptor activator activity
    directly_involved_in:
      - id: GO:0007409
        label: axonogenesis
      - id: GO:0031175
        label: neuron projection development
    locations:
      - id: GO:0005886
        label: plasma membrane
      - id: GO:0030426
        label: growth cone
    supported_by:
      - reference_id: file:human/APP/APP-deep-research-falcon.md
  - description: APP is highly expressed at synapses and plays physiological roles
      in synapse formation, maintenance, and plasticity. APP trans-dimerization
      across the synaptic cleft mediates cell-cell adhesion that contributes to
      synapse structure. APP knockout models show synaptic deficits.
    molecular_function:
      id: GO:0050839
      label: cell adhesion molecule binding
    directly_involved_in:
      - id: GO:0050803
        label: regulation of synapse structure or activity
    locations:
      - id: GO:0005886
        label: plasma membrane
      - id: GO:0043005
        label: neuron projection
    supported_by:
      - reference_id: file:human/APP/APP-deep-research-falcon.md
  - description: APP binds copper and zinc ions via its ectodomain
      (GFLD/copper-binding domain) and participates in copper homeostasis and
      reduction of Cu(2+) to Cu(+). This is a direct molecular function of the
      APP ectodomain.
    molecular_function:
      id: GO:0005507
      label: copper ion binding
    directly_involved_in:
      - id: GO:0006878
        label: intracellular copper ion homeostasis
    locations:
      - id: GO:0005886
        label: plasma membrane
      - id: GO:0005769
        label: early endosome
    supported_by:
      - reference_id: file:human/APP/APP-deep-research-falcon.md
  - description: 'ISOFORM-SPECIFIC: The Kunitz protease inhibitor (KPI) domain in
      APP751/770 isoforms confers serine protease inhibitor activity (Protease
      nexin-II function). Absent from the neuronal APP695 isoform.'
    molecular_function:
      id: GO:0004867
      label: serine-type endopeptidase inhibitor activity
    locations:
      - id: GO:0005576
        label: extracellular region
      - id: GO:0005886
        label: plasma membrane
    supported_by:
      - reference_id: file:human/APP/APP-deep-research-falcon.md
  - description: 'CLEAVAGE PRODUCT FUNCTION: Abeta peptides (particularly Abeta42)
      self-assemble into amyloid fibrils via identical protein binding. This is
      a defining biochemical property of the Abeta cleavage products of APP and
      is central to Alzheimer disease pathology. Both full-length APP and Abeta
      cleavage products engage in homodimerization.'
    molecular_function:
      id: GO:0042802
      label: identical protein binding
    directly_involved_in:
      - id: GO:1990000
        label: amyloid fibril formation
    locations:
      - id: GO:0005576
        label: extracellular region
      - id: GO:0005769
        label: early endosome
    supported_by:
      - reference_id: file:human/APP/APP-deep-research-falcon.md
  - description: APP ectodomain binds heparin and heparan sulfate proteoglycans.
      This interaction promotes APP dimerization, influences neurite outgrowth,
      and modulates cell adhesion functions.
    molecular_function:
      id: GO:0008201
      label: heparin binding
    directly_involved_in:
      - id: GO:0007155
        label: cell adhesion
    locations:
      - id: GO:0005886
        label: plasma membrane
      - id: GO:0009986
        label: cell surface
    supported_by:
      - reference_id: file:human/APP/APP-deep-research-falcon.md

APP

Gene Description

Functional Isoforms

Existing Annotations Review

Core Functions

Full-length APP functions as a cell surface adhesion molecule. APP molecules on neighboring cells engage in trans-dimerization to promote synaptogenesis and cell-cell contact. This is a physiological function of full-length APP at the plasma membrane.

APP regulates axon development through multiple mechanisms. The sAPPalpha ectodomain promotes neurite outgrowth acting as a signaling ligand, while full-length APP interacts with Fe65/Mena to guide axon growth. APP knockout mice show defects in axonogenesis.

APP is highly expressed at synapses and plays physiological roles in synapse formation, maintenance, and plasticity. APP trans-dimerization across the synaptic cleft mediates cell-cell adhesion that contributes to synapse structure. APP knockout models show synaptic deficits.

APP binds copper and zinc ions via its ectodomain (GFLD/copper-binding domain) and participates in copper homeostasis and reduction of Cu(2+) to Cu(+). This is a direct molecular function of the APP ectodomain.

ISOFORM-SPECIFIC: The Kunitz protease inhibitor (KPI) domain in APP751/770 isoforms confers serine protease inhibitor activity (Protease nexin-II function). Absent from the neuronal APP695 isoform.

APP ectodomain binds heparin and heparan sulfate proteoglycans. This interaction promotes APP dimerization, influences neurite outgrowth, and modulates cell adhesion functions.

References

📚 Additional Documentation

Deep Research Bioreason

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Bioreason Rl

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Comprehensive Research Report: Human APP (Amyloid-beta Precursor Protein; UniProt P05067)

0. Target verification (critical disambiguation)

1. Key concepts & definitions (current understanding)

1.1 What APP is

1.2 Canonical APP processing pathways

1.3 Enzymology focus (substrates, specificity)

2. Subcellular localization, trafficking, and where processing occurs

2.1 Trafficking route and compartmentalization

2.2 Why localization matters for Aβ generation

3. Physiological functions of APP and major biological processes

3.1 Synaptic development and function

3.2 Adhesion- and receptor-like functions

3.3 Trophic activity of soluble APP fragments

3.4 Mitochondria- and bioenergetics-linked biology

4. Recent developments (prioritizing 2023–2024)

4.1 “APP dyshomeostasis” framing beyond Aβ alone

4.2 Trafficking as a mechanistic bottleneck

4.3 Precision targeting of γ-secretase: modulation/stabilization vs inhibition

4.4 TBI and APP: convergence of injury biology and amyloidogenesis

5. Current applications and real-world implementations

5.1 Blood-based biomarkers reflecting APP/Aβ brain pathology (2024)

(A) Trial-ready screening use (J-TRC and BioFINDER)

(B) Memory-clinic implementation potential

(C) Commercial test validation: PrecivityAD2 (mass spectrometry)

5.2 Therapeutics that act downstream of APP: anti-Aβ monoclonal antibodies

Donanemab (TRAILBLAZER-ALZ 2; subpopulation analysis)

Plaque reduction vs clinical benefit (cross-program synthesis)

6. Expert opinions and analysis (authoritative perspectives)

6.1 Consensus and controversy: amyloid hypothesis and what it implies for APP

6.2 Where the field is heading

7. Key statistics & data (selected highlights)

7.1 Biomarker performance (plasma, 2024)

7.2 Therapeutic outcomes (anti-Aβ, 2024)

8. Evidence-supported functional annotation summary (for databases)

Summary Table

Key mechanistic figure (APP processing)

Citations

Notes